Plenaries Are Ace

Acute Renal Failure

2007-06-07T17:31:00.002Z

1.6.07

• Broadly defined as rapid deterioration of renal function resulting in accumulation of waste products such as urea and creatinine.
• Pre-renal, renal, post-renal.

Pre-renal - causes of renal hypoperfusion
• Intravascular volume depletion e.g. through vomiting, diarrhoea.
• Trauma/burns/crash injury.
• Haemorrhage.
• Pancreatitis.
• Diabetic ketoacidosis.
• Addison's disease.

Pre-renal
• Decreased CO2.
• Changes in renal vascular resistance.
• Renovascular obstruction.
• Microvascular obstruction.
• Increased blood viscosity.
• Interference with renal autoregulation.

Intrinsic ARF
• Persistent pre-renal failure of any cause.
• Nephrotoxins.
• Haemoglobinuria/myoglobinuria e.g. from any crush injury.
• Radiological contrast material.
• Acute glomerulonephritis e.g. from Goodpasture's syndrome, Wegener's granulomatosis.
• Acute renal vasculitis.
• Obstetric causes e.g. ATN from severe hypovolaemia.

Obstructive uropathy
• Bilateral urinary tract calculi.
• Single urinary tract calculus.
• Retroperitoneal fibrosis.
• Crystal nephropathy.
• Cancer of bladder/cervix.
• Urethral stone.
• Following pelvic surgery.

Clinical features of urinary tract obstruction
• Anuria.
• Polyuria.
• Alternating anuria and polyuria.
• Pain.
• UTI.
• Uraemia of no apparent cause.

Golden clinical rules
• Assess volume status.
• Search to diagnose urinary tract obstruction:
-History.
-PR.
-Ultrasound.
• If pre-renal, fill up (with saline - isotonic to plasma).
• If renal, remove cause or treat condition.
• If obstructive, relieve obstruction.

Management
• Support renal failure.
-Fluids/CVP.
-Electrolytes e.g. high plasma K+.
-Insulin/dextrose.
-Ca2+ resonium.
-Haemodialysis for uraemia.
• Look for and fight infection.
• Don't forget nutrition - enteral/parenteral.
• Remember dangers of blood-borne agents e.g. HBV, HCV, HIV.
• Renal biopsy, if indicated.
• Treat any underlying treatable condition e.g. arteritis, myeloma, hypercalcaemia.

Acute or acute-on-chronic renal failure?
• Pre-existing renal disease suggested by:
-PMH of proteinuria, Nocturia, renal stones, DM or hypertension.
-Analgesic abuse.
-FH of polycystic kidneys, hereditary nephritis.
-Normochromic normocytic anaemia.
-Secondary hyperparathyroidism.
-Stunting of growth or failure of secondary sexual characteristics.
• Palpable or history of polycystic kidneys.
• Bilaterally small kidneys.

Complications
• Fluid/volume.
• Metabolic.
• Infection.
• Nutritional.
• Related to underlying problem.
• Stressful situation for patient and family.

Prognosis
• ~40% mortality.
• Worse if:
-Post-surgery.
-Infection.
-Catabolic.
-Increase in age and multiple diseases.
-Delay in referral and commencing dialysis.
-Complications.

Survivors
• If patient survives ARF, majority recover renal function to become dialysis independent.

Pathology Of Renal Failure

2007-06-07T17:31:00.001Z

25.5.07

Renal function
• Blood supply 1250ml/min.
• GFR 150ml/min.
• Urine output 1ml/min.
• Filtration (glomerulus).
• Modification (PCT).
• Concentration (loop and DCT).
• Active processes.

Acute renal failure (ARF)
• Pre-renal - pump failure, volume loss, microvascular damage.
• Renal.
• Post-renal.

ARF: renal causes
• Ischaemia - worsened by crush injury.
• Toxins.
-Heavy metals.
-Solvents.
-Antibiotics.
-Venoms and mycotoxins.
-Bence Jones protein.

ARF: post-renal causes
• Obstruction from:
-Stones.
-Prostatic enlargement.
-Tumours.
-Ureteric stricture.
-[+Rarer causes.]

Features of ARF
• Anuria/Oliguria.
• Na+ <20mEq/L.
• High osmolality (ratio u/p >1.5).
• High urea and creatinine.
• May go on to acute tubular necrosis (ATN).

ATN
• Biochemical/laboratory features:
-Not anuric (may be polyuric).
-Urine Na+ >40mEq/L.
-Osmolality u/p <1.1:1.
-Numerous granular and cellular casts.

Chronic renal failure (CRF)
• Leakage of proteins (damage to filter).
• Na+ and water retained.
-Oedema and hypertension.
• Haematuria.
• Decrease in GFR.
-<20% abnormal (<5% = ESRF).
• Raised urea, creatinine, K+.
• Decreased Ca2+.

CRF: syndromes
• Nephritic:
-Decreased urine output.
-Modest proteinuria.
-Hypertension.
-Retention of Na+ and water.
-Haematuria.
• Nephrotic:
-Protein loss>3.5g/day.
-Hypoalbuminaemia.
-Oedema.
• Rapidly progressive renal failure.
-Generally with crescentic glomerulonephritis.

Membranous glomerulonephritis
• Nephrotic syndrome.
• Drugs, tumours, infections, SLE, DM.
• Thickened glomerular basement membrane diffusely and universally.
• Spikes (complexes) on silver stain.

Immune complex glomerulonephritis
• Circulating complexes trapped in glomeruli.
• Injury mainly due to complement binding.
• Tend to cause Membranoproliferative pattern of injury.
• See in e.g.
-SLE.
-HBV.
-HCV.
-HIV.
-Endocarditis.
-Chronic infections.
-Parasitic invasions.

Amyloidosis
• Abnormal amount of polymerised protein (β-pleated sheet).
• Plasma cell and inflammatory types.
• Trapped in glomeruli in filtration.
• Result in nephrotic syndrome.
• Stains brick red with Congo red dye.
• Apple green birefringence with Congo red.

Interstitial nephritis
• Pyelonephritis.
• Drug induced.
-NSAIDs.

Renal papillary necrosis
• Osmotic stress.
• DM.
• NSAIDs.
-Australia.
-Vultures.

Systemic hypertension
• Benign hypertension tends to have minimal effects on GFR.
• Risk increased in black people in USA.

Summary
• ARF.
• CRF.
-Polycystic.
-Systemic.
§DM, SLE, hypertension.
-Glomerular.
-Interstitial.
-Obstruction.

Glomerulonephritis

2007-06-07T17:30:00.001Z

21.5.07

Definition
• Disease affecting kidneys - classified according to changes seen in glomerulus on light, immunofluorescence and electron microscopy.

Clinical presentation
• Persistent microscopic haemuturia.
• Persistent proteinuria.
• Nephrotic syndrome.
• Recurrent macroscopic haemuturia.
• Acute nephritic syndrome.
• Acute/subacute renal failure.
• Chronic renal failure.

Proteinuria
• Normal range <0.2g/24 hours.
• Nephrotic syndrome.
• Definition: proteinuria >5g/24 hours.
• Oedema.
• Hypoalbuminaemia.
• Hypercholesterolaemia.
• Persistent proteinuria: above normal range, but not nephritic and usually asymptomatic.

Types of glomerulonephritis
• Based on histology.
• Although patients may share same histological type, clinical presentation may be variable.
• Some clinical presentations more characteristic of certain types.

Minimal change glomerulonephritis
• Usually presents as nephritic syndrome.
• Commonest cause of nephritic syndrome in children.
• Usually responds to oral steroids, if not cyclophosphamide/cyclosporin may be used.

Focal segmental glomerulonephritis
• Usually presents as nephritic syndrome.
• Responds less well to immunosuppression than minimal change glomerulonephritis.
• May be found in association with AIDS and with IVDU.
• ~50% will progress to ESRF.
• Focal segmental changes may be found late in course of patients whose initial biopsy showed minimal change glomerulonephritis.

Membranous glomerulonephritis
• Accounts for 20-30% adult nephritic syndrome and up to 5% children.
• May also present as asymptomatic proteinuria/chronic renal failure.
• In 20-30% cases, secondary to another cause.
• Up to 30% may develop ESRF.
• Up to 30% will resolve spontaneously.
• Immunosuppression reserved for those with intractable nephritic syndrome/progressive renal failure.
• Regimes include:
-Prednisolone.
-Cyclophosphamide.
-Azathioprine.
-Chlorambucil.
-Cyclosporin A.
-Mycophenolate.

Causes of secondary membranous glomerulonephritis
• Cancer: bronchus, breast, GI tract, prostate.
• Infection: hep B, syphilis, leprosy, filiriasis.
• Drugs: gold, penicillamine, captopril.
• Multisystem: SLE, sarcoidosis, RA.

IgA nephropathy
Presentation
• Often with recurrent episodes of macrohaematuria occurring within 12-24 hours of onset of URTI.
• Frequently accompanied by muscle and loin pain and fever out of proportion to severity of URTI.
• Commonest form of idiopathic GN worldwide.
• Typically affects young males M:F = 3:1.

Diagnosis
• Serum polyclonal IgA sometimes increases, but not of prognostic significance.
• On renal biopsy, mesangial deposits of IgA and C3.

Outcome
• Up to 50% adults: slowly progressive renal failure of 15-20 years of often asymptomatic progression.

Treatment
• Depends on presentation and progression.
• Immunosuppression often tried in severe nephritic syndrome/rapid progression of renal failure.

Membranoproliferative glomerulonephritis
• Usually presents as persistent proteinuria/nephritic syndrome/chronic renal failure.
• 3 histological types.
• May be secondary to systemic disease.
• Immunological abnormalities.
• Low serum, C3 complement found in 60-100% type I and 30-40% type II.
• Complement abnormalities indicate activation of alternative pathway.
• Treatment:
-If secondary to another disease, treat underlying disease.
-In idiopathic forms, no specific treatment of consistently proven benefit.

Rapidly progressive glomerulonephritis
• Form of glomerulonephritis causing renal damage - may progress from onset to ESRF within weeks/months.
• Characteristic lesion: focal necrotising glomerulonephritis with crescent formation.
• 3 main causes:
1. Antiglomerular basement membrane disease.
2. Vasculitis.
3. SLE.
• However, many other causes, including systemic disease, drugs, infections, neoplasia.
• Clinical presentation:
-Often dependent on presence/absence of systemic disease.
-If absent, patients may present with non-specific features of renal failure:
§Oliguria.
§Oedema.
§Dyspnoea/uraemic symptoms.
-Macroscopic haemuturia and loin pain sometimes reported.

Antiglomerular basement membrane disease
• Rare: affects M>F.
• May be associated with pulmonary haemorrhage.
• Characterised by presence of circulating antiglomerular basement membrane antibodies and deposition of IgG in basement membrane.

Vasculitis
• Rapidly progressive renal lesion may be seen in variety of systemic diseases, notably polyarteritis nodosa and Wegener's granulomatosis.
• Often associated with circulating anti-neutrophil cytoplasmic antibodies.

Post-streptococcal glomerulonephritis
• Occurs usually between 7 and 21 days after group A streptococcus infection.
• During epidemic, clinically detectable glomerulonephritis occurs in 5-10% after pharyngitis and ~25% after skin infections.
• Young children at highest risk.
• Presentation can vary from microhaematuria to full-blown nephritic syndrome.
• Investigations:
-Throat/skin swab.
-ASO titre.
-C3 and C4 complement may be decreased.

Alport's syndrome
• Inherited as x-linked trait.
• In males, usually progressive form of renal disease causing ESRF commonly between 16-35 years.
• Associated with sensorineural deafness and anterior lenticomus.

Renal Transplantation

2007-06-07T17:29:00.000Z

21.5.07

History
• In 01/02, Emerich Ullmann reported first case of renal autotransplantation performed in neck of dog.
• In same year, presented first xenotransplantation of kidney (goat with dog's).

First successful human kidney transplantation: Boston (1954) - identical twins.

Treatment options for ESRF
DIALYSIS
(long term)

Peritoneal Haemodialysis

TRANSPLANTATION

Cadaveric Live donor

What life is like on dialysis
• Poor quality of life.
• Usually unable to work.
• Little/no holidays.
• Feel ill most of time.

Transplantation optimum renal replacement therapy for most patients.

Cadaveric donor operation - donor selection criteria
• 2-75 years.
• No infection.
• No DM.
• No cancer except primary brain tumours.
• No HIV.

Donor selection - UK code
• Brainstem death.
• Preconditions: irreversible coma.
• Exclusions.

Imaging renal anatomy: angiogram.

Matching of kidney
• ABO.
• HLA.
• Lymphocytotoxic crossmatch.

Surgical complications
• Renal artery thrombosis.
• Renal vein thrombosis.
• Urine leak and ureteric stenosis.
• Lymphocele.

Long-term complications
• Infection.
• Cancer.
• Drug side-effects.
• Rejection.
• Graft loss.

Side-effects of immunosuppression
• Drug-specific.
• Total burden of immunosuppression.
• Additional chronic renal failure.
• Progression of primary disease.

Predictors of long-term graft function
• Factors impacting on graft survival (HLA match, donor type etc).
• Factor impacting on patient survival.

Module 2.14

2007-06-07T17:28:00.000Z

The Tax Inspector's Appointment.
21.5.07 - 1.6.07.

Drugs In Liver Disease

2007-06-07T13:46:00.001Z

11.5.07

Liver disease
• Common.
-ALD >20,000 deaths per annum.
• May need treatment.
-For liver disease and complications.
-For concomitant conditions.
• Liver is major site of drug metabolism.
-Can have major effects on drug handling.

Functions of the liver
• Processing digested foods from the intestine.
• Controlling levels of fats, amino acids and glucose.

Clinical signs of liver disease
• Jaundice.
• Ascites.

Drug handling in the body and effect of liver and kidney disease
Lipophilic drugs Hydrophilic drugs
↓ ↓
Liver Kidneys
Phase I metabolism Excretory processes
Phase II metabolism
Phase III metabolism
↓
Reduced hepatic clearance Reduced renal clearance

How are drugs metabolised?
• Phase I (oxidation, reduction, hydrolysis).
-Small chemical changes.
-FUNCTIONALISE molecule for phase II.
• Phase II (glucoronidation, sulphation, acetylation, amino acid conjugation, glutathione conjugation).
-Conjugation reactions.
-Increased water solubility.
-Increased excretion.

Functionalisation
• Addition of reactive group.
• Unmasking of reactive group.

Conjugation
• Addition of large group.
• Often charged.

Phase III: membrane transporters.
P-glycoprotein: an efflux transporter.

Effect of liver disease on drug disposition
• Severity of liver disease.
-Enormous reserve in liver.
-Affected in severe disease.
• Enzymes responsible.
-Phase II affected less than Phase I.
• Type of liver disease.
-Cholestasis (increases in alkaline phosphatase and GGT) - transporters.
-Acute hepatic inflammation (increase in transaminases) - p450 enzymes.

Effect of pharmacokinetic changes on drug effects
Liver disease
↓
Pharmacokinetic changes
↓
Clinical effect of drug
↓
Increased No change Reduced

Other effects of liver disease
• Changes in drug absorption.
-Changes in gut motility.
-Delay in gastric emptying and orocaecal transit.
• Changes in protein binding.
-Hypoproteinaemia.
-Affects drugs with high protein binding.
• Changes in liver blood flow.
-May be decreased/bypass liver.
-Increased bioavailability of certain drugs.
• Changes in renal excretion.
-Affected in severe liver impairment.
-Etc.

Effect of pharmacodynamics changes in liver disease
Liver disease
↓
Pharmacodynamic effects
↓
Exaggerated response Reduced response Increased toxicity
↑ ↑ ↑
Sedation with Decreased diuresis with Nephrotoxicity
benzodiazepines loop diuretics with aminoglycosides

Use of potentially hepatotoxic drugs
• Not an increased risk of further liver damage when administered hepatotoxic drugs.
• Decreased hepatic reserve therefore, more severe clinical consequences of any damage.
• Judicious use.

Using drugs in liver disease
• Careful clinical assessment always important.
• Questions to ask:
-How serious is the condition, and what if the treatment was withheld?
-What drug treatments are available?
-Are efficacies of different treatments equivalent?
-What are the adverse effects of different treatments?
-Is the drug metabolised by the liver?
-Is the drug potentially hepatotoxic?

Simple rules in liver disease
• Determine whether dose needs to be decreased (see appendix in BNF).
• Start at low doses and increase dose slowly, depending on response and adverse effects.
• Carefully monitor patients and review regularly.
• Avoid interacting drugs.
• Provide information for patients.
• Contact in case of problems.
• Consider drugs in differential diagnosis if new symptoms.

Practice points
• Liver disease affects both pharmacokinetics and pharmacodynamics parameters, both of which increase risk of drug toxicity.
• Doses of lipophilic drugs should be decreased, particularly for those with narrow therapeutic index.
• First-pass metabolism of drugs with high hepatic extraction decreased, necessitating decrease in dose of oral formulations.
• Choose hydrophilic drug over lipophilic compound when available.

Blood-Borne Viruses

2007-06-07T13:45:00.001Z

11.5.07

• HIV.
• Hep B.
• Hep D.
• Hep C.
• Parvovirus etc.

AIDS
• Acquired Immune Deficiency Syndrome.
• First cases recognised in 1979.
• First paper 1981.

Does HIV cause AIDS?
Cons:
1. For each person with AIDS there are 99 who are HIV-infected.
2. HIV-positive AIDS cases (4 in total) - HIV is just another opportunist growing in AIDS patients.
Pros:
1. Cohort studies.
2. Therapy.

"AIDS viruses"
1983: Montagnier - Paris.
LAV (lymphodenopathy associated virus).
IDAV (immune-deficiency associated virus).
1983: Gallo - USA.
HTLV-III (human T-cell leukaemia virus III).
1984: Gallo.
HTLV-III (human T-cell lymphotrophic virus III).
1986: HIV-1 (human immunodeficiency virus-1).
HIV-2.

Retrovirus
Genome: RNA positive sense (2 copies per virion).
Envelope: Yes.
Capsid: Cuboidal.
Size: ~ 100-120 nm.

Classification
1. Spumaviruses.
2. B and D-type oncoviruses.
3. C-type oncoviruses.
4. HTLV-related oncoviruses.
5. Lentiviruses (SIV, HIV etc.).

HIV genes and proteins
GAG (Group specific antigen.)
Encodes capsid proteins. Made as long polyprotein and cleaved to p24,
p17, p15.
Pol (Polymerase.)
Encodes protease, reverse transcriptase, endonuclease/ligase.
Env (Envelope.)
Encodes envelope glycoproteins (gp). Made as gp160, which is cleaved to
gp120 and gp41.

Stages in infection
1. Attachment - 2 receptors.
2. Penetration - fusion/endocytosis.
3. Reverse transcriptase - produces provirus.
4. Integration.
5. Reactivation and new virus production.
6. Maturation - proteolysis.
7. Release - budding.

HIV - receptors
1. Initial binding by gp120 to CD4.
2. Conformational change to gp120 and gp41 exposes new ligand.
3. Ligand binds to chemokine receptors e.g. CCR-5.
4. Viral entry.

Cells infected
1. Lymphocytes (T-helper cells expressing CD4).
2. Monocytes and macrophages.
3. Brain cells (predominantly astrocytes and oligodendrocytes, but also neurones).
4. Enterocytes.
5. Laryngeal cells.

Human infection
1. Initial acquisition (sexual, blood etc).
2. Incubation period (4-6 weeks). Each day 109 - 1010 new virus particles produced (106 - 107 are mutant).
3. Seroconversion illness in only 50% of those infected. Resembles glandular fever.
4. Latent period (virus still excreted).
5. Development of AIDS. Rising viral load, falling CD4 counts.

HIV excretion
1. Semen.
2. Cervical secretions.
3. Blood.
4. CSF.
5. Breast milk.
6. Saliva.
7. Urine.
8. Faeces.

Module 2.13

2007-06-07T13:44:00.000Z

The Yellow Clerk.
8.5.07 - 18.5.07.

Alcohol's Trip Through The Body

2007-06-06T17:46:00.001Z

27.4.07

Beer
1. MOUTH: usual ingestion route.
2. STOMACH: little absorption/breakdown here. Most emptied to small intestine.
3. SMALL INTESTINE: uptake into bloodstream.
4. BLOODSTREAM: carries the alcohol.
5. LIVER: oxidises alcohol into water, carbon dioxide and energy at 0.015%/hour.

Alcohol - access to body
• Ingestion.
-Slowly absorbed from stomach.
-Rapidly absorbed from small intestine.
• Other routes of entry:
-Skin.
-Nasal passages/lungs.
-Other epithelia??

How to measure alcohol consumption?
• Units/grams.
• 1 unit = 8g of alcohol.

"Safe limit" for alcohol?
• In healthy male, no more than 28u/week.
• In healthy female, no more than 21u/week.

Ethanol
• Provides "empty" calories - no nutritional benefit.
• 7 cal/g - almost as high as fat in calorific content.
• Water-soluble - does not enter fat.
• Size and body build affect uptake.

Absorption of alcohol
• Rate-dependent on alcohol type and concentration.
• Peaks 1 hour after consumption.
• Faster with carbonated alcohol.
• Greater with empty stomach.
• Increased by drugs enhancing gastric emptying and those drugs that inhibit gastric alcohol dehydrogenase.
• Retarded by food, especially carbohydrate (as much as 75% compared to an empty stomach).

Distribution of absorbed alcohol
• Distribution throughout water in body.
• Most tissues exposed to same concentration of alcohol as blood.
• Liver has higher exposure due to portal system.

Elimination of absorbed alcohol
• 2-5% excreted unchanged in urine, sweat, faeces, milk or breath.
• 95% metabolised by liver.

Alcohol breakdown in liver
• ADH and ALDH2 metabolise ethanol consumed.

ADH ALDH
• Ethanol Acetaldehyde Acetate.
• ADH variants found in most tissues, but highest in liver.

Alcohol metabolism
• 1st step: oxidation of ethanol to acetaldehyde, catalysed by ADH containing NAD+.
• Conversion of acetaldehyde into acetate by ADLH also results in generation of NADH.
• NADH = Hydrogen-transfer chemical enabling oxidative phosphorylation to take place.

ADH
• Up to 50% Japanese people lack ADH.
• Inheritance of high activity ADHb2 enzyme, encoded by ADH2*2 gene, and inactive ALDH202 gene product conclusively associated with decreased risk of alcoholism.

Alcohol metabolism has powerful effects on cellular energy production pathways
• Drinking alcohol warms people up - rapid NADH production from alcohol dramatically increases energy availability and body temperature.

Excess NADH can block other normal metabolic pathways
1. Convert pyruvic acid to lactic acid.
-Hepatic gluconeogenesis inhibited.
-Glucose production decreased.
-Risk of hypoglycaemia.
-Overproduction of lactic acid blocks uric acid excretion by kidneys. Acidosis.
2. Inhibits lipogenesis.
-Accumulated fatty acid converted into ketones and lipids.
-Heavy drinkers ketotic and overweight.
3. Makes excess ATP.
-Inhibits fat oxidation and citric acid cycle.
-Accumulated fatty acids/acetyl coA → ketones and lipids.
-Excess fat in liver and blood.

Metabolism of alcohol faster in heavy drinkers
• Normal metabolism increased, generating high blood concentrations of acetate.
• Microsomal ethanol oxidising system.

Alcohol damages GI tract
• Causes inflammation of tongue, stomach, pancreas, liver and intestines.
• Breakdown products lead to fat deposition, fibrosis and scarring of liver.
• Impairs digestion of food and absorption into blood etc.

Alcoholic hepatitis
• Inflammation induces accumulation of extracellular matrix) collagen - liver fibrosis.
• Scar tissue forms.

Therefore, cirrhosis
• Growth of connective tissue destroys liver cells.

Signs
• Jaundice.
• Fluid in belly.
• Haematemesis.
• Confusion.
• Spider naevi.
• Gynaecomastia.

Oesophageal varices
• Abnormal dilatation of vein due to increase in portal vein pressure.
• Can cause life-threatening bleed.

Alcohol intoxication
• Elation, euphoria, stimulation of pleasure and reward centres in brain.
• Altered behaviour, personality, aggression etc.
• Sedation - mild anaesthetic.

Blood alcohol and brain
• Cerebral impairment at 0.1%.
• Damage of information exchange between cerebellar cortex and cerebrum, at 0.15-0.35%.
• Medulla function depressed - can occur at levels as low as 0.30%.

Alcohol on the brain
• Increased dopamine release to cause euphoria.
• Inhibits glutamate receptor function - when blocked, results in cognitive impairment and amnesia.
• Potentiates GABA receptor function - site of action of sedation and anaesthesia.
• Increased release of 5-HT (serotonin), causing one to become sleepy.

Physiological changes accompanying alcohol consumption
• Sweating, flushing, bruising.
-Body can suffer from heat loss and hypothermia.
• Tachycardia and increase in blood pressure.
• Kidneys secrete more urine.

Alcohol and sex
• Decreased sexual performance.
• Loss of libido.
• Can lead to impotence/less sperm.
• Atrophy of testicles.
• Decreased vaginal lubrication.
• Poor decision increase risk of STDs.
• Menstrual abnormalities.
• Alcohol during pregnancy causes complication for fetus.
• Breast cancer risk factor for females who engage in even moderate drinking.

Alcoholic Pancreatitis

2007-06-06T17:45:00.001Z

23.4.07

Alcoholic pancreatitis
Epidemiology
• 40 per 100,000/year.
• Associated with alcohol abuse - binge drinking.
• Increasing incidence.
• Severe in 20-30%.
• Mortality up to 10%.
• Management variable.
• Treatment inadequate.

Aetiology
• Alcoholic.
• Biliary - gallstones.
• Idiopathic.
• Others, including hypercalcaemia and hyperlipidaemia.

Alcohol consumption
Binge drinking
• People living in north of England more likely to die earlier through alcohol abuse than anywhere else.

The problem
• Rates of acute pancreatitis increased from 4.9-9.8/100,000.
• Particularly large increase in younger people.

Alcoholic pancreatitis
Clinical signs
• Upper abdo pain.
• Epigastric/diffuse abdo tenderness.
• Serum amylase activity (4X normal).
• Cullen's sign.
• Grey-Turner's sign.

Complications
• Pancreatic necrosis.
• Infected necrosis.
• Pseudocyst.
• Haemorrhage.
• Multiorgan failure.
• Death.

Non-surgical therapy
• Resuscitation.
• Analgesia.
• Stone extraction.
• Ventilation.
• Inotropes.
• Dialysis.
• Nutrition.

Major intervention
• Open necrosectomy.
• Minimal access necrosectomy.
• Pancreatic stenting etc.

Limitations to current management
• Prophylaxis restricted to removing precipitating factors after onset.
• No significant impact on course of disease made by medical treatment.

Pathogenesis
• Autolysis precipitated by known factors.
• Activated digestive enzymes within and subsequently around acinar cells.
• Co-localisation of granules and Lysosomes.
• Vacuolisation etc.

Premature digestive enzyme activation critical
• Mutations in cationic trypsinogen render trypsin resistant to inactivation.

Ca2+ hypothesis
• Abnormal, prolonged elevation of cytosolic Ca2+ initiates pancreatitis.

Alcohol-induced injury theory
• Spasm of sphincter of Oddi.
-Duodenal-pancreatic reflux.
• Formation of protein-rich secretory plugs.
• Duct obstruction causes pancreatic damage and altered Ca2+ signalling.
• Generation of free radicals.
• Sensitisation of acinar cell to CCK on zymogen conversion in vitro.
-Ethanol may sensitise CCK-induced zymogen conversion in pancreatic acinar cells.
• Toxic metabolites.

High ethanol/unsaturated fatty acid diet induces pancreatitis in rats.

Fatty acid ethyl esters induce:
• Direct pancreatic damage in vivo.
• Prolonged abnormal increase of Ca2+ concentration.

Alcohol Dependence: Approach To Detection And Treatment

2007-06-06T17:44:00.000Z

23.4.07

Definitions
1. Hazardous drinker: heavy/binge drinkers with drinking patterns that pose considerable risks to their own and others' health.
2. Harmful drinker: clear evidence that alcohol use is responsible for (or substantially contributes to) physical/psychological harm - may lead to disability or have adverse consequences for interpersonal relationships.
3. Dependent drinker:
-SADQ.
-DMS IV-R.
-ICD-10 - used in all hospital admissions.
-?AUDIT.

Reasons for detecting alcohol dependence
• Failure to detect may lead to:
-Unnecessary investigations.
-Alcohol withdrawal syndrome.
-Recurrent harm (end-organ damage).
-Recurrent hospital attendance.
• Liver deaths have increased eight-fold in 3- years.
• 50% subjects die before they have a chance to stop drinking.
• Prevention of unexpected alcohol withdrawal.

Methods of detection
• History and examination.
• Clinical investigations.
• Screening/assessment questionnaires.

History and examination
• Clinical findings often completely normal.
• Clinical findings poor as early indicators of alcohol - WHO, 1987.

Clinical investigations - laboratory markers
• Blood/urine/breath alcohol:
-No information regarding severity.
-Objective evidence of recent drinking.
-Low sensitivity.
• Serum gamma glutamyl transferase (GGT).
• MCV.
• Carbohydrate-deficient transferring (CDT).
• Conventional lab tests of no use for detecting alcohol abuse/dependence. Also, %CDT cannot be used as screening instrument - Br J Gen Pract 2001 Mar.
• Lab tests useless as screening tools with sensitivities between 10% (%CDT) and 52% (GGT) - Acta Clin Belg 2002 Sep-Oct.

Screening questionnaires
• Paddington Alcohol Test (PAT):
-Staged approach.
-1 min to complete.
-A+E departments.
-Detect hazardous and harmful drinkers.
-46% of detected and referred patients re-attend.
-Constant audit and feedback improves use.

PAT staged approach
• Fall.
• Assault.
• Psychiatric.
• Repeat attender.
• Collapse.
• GI.
• Cardiac.
• Head injury.
• Unwell.
• Self-neglect.

Triggers - AAFs
• Gastritis.
• Hypertension.
• Depression.
• Stroke.
• TB.
• DM.
• Falls.

FAST alcohol screening test
• Staged approach.
• 1 min to complete.
• Sensitivity of 91%.
• Used in wide variety of settings, mainly research.

CAGE questionnaire
• 4 questions.
• More sensitive than routine lab markers.
• Insensitive to milder alcohol abuse.

Alcohol use disorders
• 10-item questionnaire.
• 10 min to complete.
• Score >8 highest sensitivity.
• Identifies hazardous drinking earlier and with greater sensitivity than:
-FAST/CAGE questionnaires.
-Routine history taking.

Screening questionnaire
• Drinking risky amounts was common (17%) in medical inpatients. Most drinkers of risky amounts had dependent (77%), but not the broad spectrum of unhealthy alcohol use anticipated.
• AUDIT reliable tool in detecting dependency.
• AUDIT cut-off of >16-19.

Assessing dependence
• DSM IV.
• ICD-10.
• Severity of alcohol dependence questionnaire (SADQ).

Assessing withdrawal
• Alcohol withdrawal symptom checklist:
-Nervousness.
-Sweating.
-Tremor.
-Nausea.
-Vomiting.
-Abdo pain.
-Seizures.
-Poor appetite.
-Hallucinations.
-Irritation.
-Confusion.
-Chill.
-Headache.
-Craving etc.

Risk factors for progression to severe withdrawal
• High alcohol intake.
• High levels of anxiety.
• Sweating (palms).
• History of severe withdrawal including seizures/delirium tremens.
• Hypoglycaemia.
• Insomnia.
• Concomitant use of other psychotropic drugs.
• Hypokalaemia.
• Tachycardia etc.

Aim for treatment
• Give support and advice for detox.
• Deliver brief interventions.
• Develop and maintain timely, effective, safe interventions.
• Train/support contemporaneous treatment.
• Referral to specialist services.
• Liaison with GPs.

Drugs of choice
• Chlordiazepoxide.
-Oxazapam if liver damage.
• Thiamine - oral/parenteral.

AWS - stages
Usual time from stopping drinking to onset Most common features
Stage 1 6-8 hours Autonomic hyperactivity, manifest in sweating, anxiety and tremor. Tremor and anxiety.
Stage 2 10-30 hours Neural excitation, including hallucinations, hyperactivity and insomnia.
Stage 3 36-70 hours Grand mal seizures
Stage 4 36-70 hours Progression to delirium tremens

Module 2.12

2007-06-06T17:42:00.000Z

Hitting The Bottle.
23.4.07 - 4.5.07.

CPC: Module 2.11

2007-03-10T12:30:00.001Z

2.3.07
Fitness factors
• Body weight:
-BMI measurement in kg/m2.
-Diet.
• Cardiovascular fitness.
-CVS (cardiac output 5.30L/min).
§Heart rate.
§Stroke volume.
-Lungs (ventilation 5-25L/min).
§Vital capacity.
§Flow rate - altitude and erythropoietin.
• Skeletal muscle.
-Hypertrophy.
-Microtrauma.
-Glycogen.
• Mental attitude.
-Positive thinking.
-Endorphin effect.

Lung diseases affecting fitness - pulmonary dysfunction
• Pulmonary oedema (secondary to cardiac failure).
• Asthma.
• COPD.
-Emphysema.
-Chronic bronchitis.
• Pulmonary fibrosis.

Heart failure
• Starling's law.
• Oxygen use by:
-Heart itself.
-Other tissues.
• Possibility of reversibility.
-LVAD device.

Metabolic syndrome
• Group of risk factors in one person.
-Central obesity.
-Abnormal lipids (high triglycerides and low HDL cholesterol) → atheroma.
-BP >130/85.
-Insulin resistance.
-Prothrombotic blood state.
-Elevated CRP.

Type II diabetes mellitus
• Genetic factors (concordance).
• Abnormal glucose load response.
• Insulin resistance (?reduced transporter protein).
• Elevated, but eventually insufficient insulin.
• >80% patients obsess.
• Amylin deposition in islets late on.

Energy Expenditure, Exercise And Weight Loss

2007-03-10T12:29:00.000Z

2.3.07

• Basal metabolic rate (BMR): basic level of metabolic activity required to stay alive.
• At cellular level:
-Pumping ions across membranes.
-Turnover of proteins etc.
• At organ level:
-Pumping blood.
-Respiration.
-Muscle tone.
• BMR closely regulated to amount of non-fat tissue in body.
• Measured after overnight fast, at comfortable temperature, with subject awake and resting.

Schofield equations - different for different age groups and gender

Total energy expenditure (TEE)
• During sleep, EE lower than BMR.
• All other time, EE>BMR.
• EE increased by:
-Performance of external work.
-Heat generated by work.
-Ingestion of meals (dietary-induced thermogenesis - DIT).
• TEE = BMR + physical activity + DIT.
• BMR usually largest component of TEE.
• To estimate TEE due to physical activity, multiply energy of each by time spent of each activity.
• PAL (physical activity level) = Ratio of overall daily TEE to BMR.

Mobilisation of fat stores
• Mismatch of energy supply to energy demand.
• Therefore, energy stores must be mobilised.
• Adequate carbohydrate intake in diet will partially maintain glycogen stores.
• Smaller meals mean absorptive period shorter:
-Insulin concentration decreased and glucagon concentration increased.
-Leads to activation of hormone-sensitive lipase.

Triglyceride NEFA (non-esterified fatty acids)
CO2/ketone bodies

Liver

Glycerol Triglyceride

Muscle
Co2
Kidney

Liver Glucose

• Extent to which this continues (and protein breakdown spared) depends upon:
-Size of energy gap.
-Duration of decreased intake.
-Maintenance of physical activity/energy expenditure.

Integrated view of metabolism: metabolic diary
1) Waking up: post-absorptive state
• Plasma glucose and insulin at lowest in 24-hour cycle.
• Plasma NEFA at highest.
• Glucose enters blood from liver glycogenolysis and hepatic gluconeogenesis.
• Blood glucose used by brain and red blood cells.
• Skeletal muscle mainly uses NEFA for energy.
• Some breakdown of protein in muscle due to low insulin.
• Some amino acids oxidised and amino group transferred to pyruvate → alanine → liver → gluconeogenesis.

A) On holiday - plenty of food, not much exercise
2) Breakfast - carbohydrate, protein and plenty of fat
• Glucose and amino acids increase in blood in 15-30 minutes.
• Plasma glucose will remain somewhat elevated for 3-4 hours.
• Plasma insulin concentration rises.
• Glucagon secretion falls.
• Glycogen metabolism switches to synthesis.
• Increased insulin, decreased lipase activity and decreased release of NEFA.
• Increased muscle uptake of glucose and amino acids → glucose oxidation, protein and glycogen synthesis.
• Arrival of chylomicron triacyl glycerol.
• Insulin stimulates lipoprotein lipase → fatty acid uptake → triacyl glycerol storage.
• 4 hours post-meal, fat storage at maximum.

3) Lunch.
• Insulin-stimulated processes primed.
• Reinforces pattern of storage.
• Plasma NEFAs remain suppressed.
• Glycogen synthesis continues.
• Storage of TAG in adipose tissue continuous.

4) Dinner.
• Virtually no break in storage of nutrients.
• At end of day, replete +++.

B) Energetic day and healthy diet
2) Breakfast - mainly carbohydrate with little fat
• Sharper rise in glucose and insulin.
• Release of NEFAs suppressed.
• Preservation of adipose tissue TAG stores.

3) Some gentle exercise (walk/cycle to work)
• Some glycogen breakdown.
• Increased heart rate and concentration.
• Blood flow to muscle increases, delivering more substrate.
• Skeletal muscles require more substrate.
• More glucose uptake from plasma.
• Increased sympathetic activity and adrenaline → fat mobilisation.
• Plasma glucose decreased → insulin decrease→ less conservation of fat.
• Less suppression of glucagon by glucose.
• Change from high insulin: glucagon ratio with intense substrate storage, to lower ratio with less storage and diversion of substrate to muscle.

4) Lunch (low-fat)
• Metabolic system less primed for storage.
• Afternoon walk will divert more substrate into oxidisation.
• At end of day, less substrate will have been stored, and more oxidised.

Summary
• Storage of energy regulated.
• Body's immediate needs met.
• Surplus stored in integrated way.
• Integration for utilisation - energy available for activity as required.

Energy Balance And Body Composition

2007-03-10T12:28:00.002Z

26.2.07

Body weight = Fat + Fat-Free Mass
0.900g/cm3 1.100g/cm3

Estimating total body fat: whole body density (typical figure: 1.024g/cm3). Methods:
• Underwater weighing - gold standard.
• Skinfolds - not direct measures of body fat - callipers - four sites:
-Biceps.
-Triceps.
-Subscapular.
-Iliac.
• Total body volume.

Estimating total body fat
• Total body water: inverse relationship between body water and fat.
-FFM = TBW/0.73.
• Total body potassium: gives idea of FFM - radioactive K40.
-Women: FFM = TBK/60.
-Men: FFM = TBK/66.
• Bioimpedance: more fat, greater resistance to electrical climate - if subject dehydrated, poor result.
• Ultrasound.
• X-rays.
• Dual energy x-rays (DeXA).
• MRI scans.
• CAT scans.

Estimating lean body mass
• Total body potassium (K40).
• Total body nitrogen: in vivo neutron activation analysis.

Estimating carbohydrate stores:
• Muscle biopsy.

Assessing body composition using BMI
• BMI = Weight (kg) / Height2 (m2).
• Not direct measure of body fat, but useful.
• Cutoffs:
-<20: underweight.
-20-24: "normal."
-25-29: overweight.
-30+: obese.
• NB1: athletes.
• NB2: children - Cole et al (2000) BMJ 320; 1-6.
• NB3: it's not just how much fat - it's where!

Energy balance
• Intake - output = Δstore
Protein BMR (basal metabolic rate) glycogen
Fat HIF (heat increment of feeding) fat
Carbohydrates activity
Alcohol
• Metabolisable energy.
Protein Fat Carbohydrate Alcohol
4 9 3.75 7 kcal/g
17 39 16 27 MJ/g

Losing weight
• Negative energy balance:
-Decreased intake.
-Increased expenditure.
-Decreased intake AND increased expenditure.

What is feasible?
• Energy deficit of 4.2MJ (1,000kcal)/day for 3-6 months.
• -29MJ (7,000kcal)/week = 1kg loss/week.
• Total loss ~5.20kg.
• After: Lean (1998) Handbook of Weight Management.
• NICE Guidelines: December 2006.

Module 2.11

2007-03-10T12:28:00.001Z

The Middle Manager's Resolution.
26.2.07 - 9.3.07.

Clinical Molecule Genetics

2007-03-10T12:27:00.002Z

23.2.07

Molecular genetics laboratory
• Sample (blood, buccal cells, muscle biopsy, fixed tissue, CVS, amniotic fluid, hair roots).

• DNA.

• Analysis (PCR, DNA hybridisation, DNA sequencing).

• Result (interpretation - allele sizing, risk calculation, unknown mutation).

• Report.

Methods of DNA analysis
• DNA amplification (PCR).
• DNA hybridisation.
-Genomic Southern blotting.
-DNA Microarrays (DNA chips).
• DNA sequencing.

DNA Microarrays
• 100,000+ oligonucleotide "probes" on microchip.
• Uses include:
-Expression studies.
-Rapid linkage analysis - SNPs.
-SNP analysis for pharmacogenetics.
-DNA sequencing.

Types of mutation
• Large-scale rearrangements.
-Deletions, duplications.
-Inversions.
• Point mutations.
-Base substitution.
-Small deletion/insertion.
• Expanding Trinucleotide repeats.
• Imprinting.

Deletions
• Part/whole of gene.
-DMD - ~66% cases.
-SMA - 95% cases = homozygous deletion.
• Large deletions of several genes.

Duplications
• Part/whole of gene.
-HMSN Ia - ~70% cases.
• Often reciprocal to deletion.
-HMSN/HNPP.

Inversions
• Part/whole of gene.
-Haemophilia A.
• Often many genes.

Point mutations
• Base substitution (SNPs).
-Nonsense mutation (creates stop codon).
-Misssense mutation (changes one amino acid).
-Silent mutation (no effect on protein).
-Splice site mutation (leads to exon slipping/translation of intronic sequence).
-Regulatory region mutations.
-Frameshift mutation.
• Small deletion/insertion.
• Single base change in promoter.
• Can lead to increase/decrease in protein product.
• Leads to milder forms of genetic disease.
• Likely to be involved in polygenic disorders.

Pathogenesis: CF mutation types
Expanding trinucleotide repeats
• Usually polymorphic - tend to be neurological consequences.
• CAG = HD/SCAs/SBMA (affected range 40-120 repeats).
• CTG - Myotonic dystrophy.
• CGG - Fragile X.
• Inheritance:
-Autosomal dominant.
-Autosomal recessive.
X-linked recessive.
-X-linked - Fragile X.
• Location:
-Exonic.
-Intronic.
-Close to gene.

Imprinting
• Maternal and paternal copies of gene differentially imprinted.
• Very few genes imprinted.
• Mechanism is methylation - silences gene.
• Imprint lost in germ cells.
• Imprinting-related disorders include Prader-Willi and Angelman syndromes (15q 1.4).
• Uniparental disomy.

Molecular genetics - types of analysis
• Known mutation.
-E.g. common point mutation, deletion/duplication, triplet repeat expansion.
-Set up mutation-specific assay. Relatively easy.
• Unknown mutation.
-Screen for changes.
-DNA sequencing.
• Linkage analysis.
-Family studies using polymorphic markers linked to gene of interest.

DNA polymorphic markers
• Identity testing.
• Rapid chromosome aneuploidy screening.
• Linkage analysis.

Potential problems for DNA analysis
• Germ line and somatic mosaicism.
• Genetic heterogeity.
-E.g. retinitis pigmentosa >20 genes to date.
• Sensitivity of mutation detection.
-Size of gene, limits of current technology.
-Cryptic splice sites.
• Pathogenicity of missense mutations.
• Linkage: recombination/new mutation.

Future developments
• Proteomics/metabolomics.
• Genetics of common disease.
-Susceptibility/risk factors.
• Pharmacogenetics.
-Adverse reactions/tailored drug therapy.
• Oncology.
-Acquired mutations.
-Tumour expression profiling.
• Gene therapy.

New technologies
• Electronic hybridisation.
• Microarrays.
• Comparative Genome Hybridisation (CGH).
• Mass spectrometry (1 million SNPs per day).
• Individual genome sequence.

Variation In Response To Drugs

2007-03-10T12:27:00.001Z

19.2.07

What is pharmacogenetics?

We all vary in response to…
• Environmental chemicals.
• Nutrients.
• Drugs…

• ~15% smokers develop lung cancer.
• 20% of alcoholics will develop liver cirrhosis.
• With medicines:
-Patients may respond well.
-Patients may not respond at all.
-Patients may respond adversely.

Variability is an issue for:
1. Drug efficacy.
2. Drug safety.

"One dose fits all" - variable efficacy
• 6.5% (n=1225) admissions due to adverse drug reactions.
• Seven 800-bed hospitals occupied by adverse drug reaction patients.
• Cost £446m per annum.
• Death in 0.15% - equivalent to 5700 deaths per year.

Definitions
• Pharmacogenetics = Study of genetic basis for difference between individuals in response to drugs.
• Pharmacogenomics = Used in wider sense.

"The right medicine for the right patient"
• Rapid sequencing for specific gene polymorphisms.
• Knowledge of genetic sequences of target genes coding for enzymes, ion channels etc.

• 3 billion base pairs contain all information necessary to make a human being.
• Similarities and differences: 99.9% same, 0.1% different.

Potential benefits
1. Drug efficacy.
2. Drug safety.
3. Pharmacoeconomics.
4. Drug development.

Continuous variability
• Some patients: usual response.
• Some patients: less-than-usual response.
• Some patients: more-than-normal response.
• Continuous distribution.

Factors
• Genetic and environmental.
• Multiple genes.
• Race.
• Sex.
• Diet.
• Weight.
• Etc…

Discontinuous variability
• Discrete proportion (large/small).
• Respond differently from rest.
• Most often single gene.
• Genetic polymorphism.
• Mutation >1% of population.
• Simple inheritance.
• Two or more discontinuous forms.

Some examples
• Cytochrome p450 oxidation.
• Acetylation.
• Porphyrias.
• Abacavir hypersensitivity.

CYP 2DG
• Defective oxidation.
• First identified in debrisoquine.
• Extensive metabolisers (most).
• Poor metabolisers.
• Intermediate metabolisers.
• Ultra-rapid metaboliser.
• Variability in drug concentrations.
• Ethnic variability (6% in white populations).
• Metoprolol.
• Codeine.
• Haloperidol.
• Flecainide.
• Nortriptyline.
• CYP 2C9.
• Warfarin.
• Most sulphonylureas.

Acetylator status
• Important route of metabolism.
• Rapid/slow acetylators.
• Ethnic variability again:
-90% Japanese rapid acetylators.
-50% Western rapid acetylators.

Porphyrias
• Congenital/acquired disturbances in haem biosynthesis.
• Concomitant environmental/genetic factors.
• Acute = Neurovisceral presentation.
• Cutaneous = Photosensitive skin lesions.

Acute intermittent porphyria
• Autosomal dominant.
• Variable penetrance.
• PBG deaminase = Deficient enzyme.
• Enormous number of mutations found to be associated with acute intermittent porphyria - family specific.
• No accurate calculation of frequency.
• Acute intermittent porphyria most common acute porphyria.

Provocative factors
• Alcohol.
• Many drugs.
• Barbiturates.
• Anticonvulsants.
• Oestrogens (including OCP).
• Infection/surgery.
• Low-carbohydrate diets/fasting.

Abacavir hypersensitivity
• Nucleoside reverse transcriptase inhibitor used in HIV disease.
• 5% patients develop hypersensitivity reaction within 6 weeks.
• Rechallenge results in more serious reaction.
• HLA-B*5701 = Genetic predisposing factor (odds ratio of 29).

Thioprine methyl transferase (TPMT)
• Metabolises azathioprine and 6-mercaptopurine.
• Critical pathway in haemopoietic tissue.
• Associated with severe haemopoietic toxicity.

Clinical Cytogenetics

2007-03-10T12:26:00.000Z

19.2.07

What is cytogenetics?
• Study of chromosomal pathology.
• Chromosomes are protein/DNA macromolecules.
• They carry genes.
• When they mutate, they cause phenotypic changes - some are recognised as syndromes.
• Constitutional changes.
• Acquired changes.

Cell and tissue culture
• There are a variety of tissues received in the Cytogenic laboratory, which include:
-Blood - lymphocytes.
-Amniotic fluid - foetal cells.
-Chorionic villus.
-Bone marrow.
-Products of conception, skin and tumour tissue.
• Most cells and tissues need to be cultured - exception to this:
-Bone marrow cells.
-Trophoblasts seen in chorionic villus tissue.

Investigations on blood samples
• Neonates - know syndromes and unexplained dismorphism and/or congenital abnormalities.
• Childhood developmental/intellectual delay.
• Pubertal failure.
• Infertility.

Prenatal diagnosis
• Indications for prenatal diagnosis include Downs risk from sera screening.
• Abnormalities seen on ultrasound scan.
• Known carriers of single gene/chromosomal disorder.
• Parents who have had previously chromosome-affected child.

Methodologies
1. Cell culture: mitotic cell division stopped at metaphase.
2. Stain by G banding: molecular Cytogenic - special identity by FISH.
3. Microscopy: molecular genetic methods e.g. MLPA, RTFCR.
4. Microarrays.
5. Write detailed interpretative reports.

Cell and tissue culture
• Aspects to be considered in cell culture include:
-Sterility - aseptic techniques, biological safety cabinets, antibiotics.
-Culture vessels - plastic/glass.
-Culture media - provides nutrients, maintains pH.
-Temperature - 370C maintained using incubator.
-Culture environment - carbon dioxide and oxygen levels can be altered.
-Mitogens.
-Harvesting procedure.
-Stop cells growing at metaphase using colcemid.
-Hypotonic solution swells cells.
-Fixative (methanol/acetic acid).

Molecular cytogenics - fluorescence in-situ hybridisation (FISH)
• Hybridises probes with complementary sequences to target DNA.
• Procedure consists of:
-Denaturation.
-Hybridisation.
-Stringency washing.
-Visualisation.
• Extend cytogenetic analysis to non-dividing cells.

New technologies - arrays
• Array CGH, BAC arrays and oligonucleotide arrays.
• Arrays consist of specific DNA sequences, which may be spotted onto a glass slide/some other substrate.
• Hybridisation with target DNA then performed.

What might cause non-disjunction?
• Failure of chromosomes to separate at meiosis I/chromatids at meiosis II.
• Asynapsis = Failure of chromosomes to pair.
• Asynapsis can be deduced by observing that number of chiasma reduced/non-existent.
• Can be estimated by recombination frequency - known that older women (>35 years) have half number recombinations compared to younger women.

Viable trisomy conditions
• Trisomy 21 = Down's.
• Trisomy 13 = Patau.
• Trisomy 18 = Edwards.

Sex chromosome aneuploidy
• 45, X = Turner.
• 47, XXX = Triple X.
• 47, XXY = Klinefelter.
• 47, XYY.

X chromosome inactivation
• In normal female with 2Xs, one X inactivated.
• In male with Klinefelter, one X inactivated.

Chromosomal abnormalities (structural)
• Deletion.
• Duplication.
• Isochromosome.
• Inversion.
• Translocation.

Deletions
• Deletion with >2% of total haploid genome will result in lethal outcome.
• Smallest viable loss from chromosome ~4Mb.
• Therefore, large number of contiguous genes lost, resulting in intellectual retardation and congenital malformations.

Microdeletions
• Describes small chromosomal loss only detectable by FISH.
• Well-described syndromes include:
-Prader-Willi.
-Angelman.
-William's.
-Wolf Hirschorn.
-Cri-du-chat.
-DiGeorge.
-Miller Dicker.

Reciprocal translocations
• Associated with:
-Impaired spermatogenesis.
-Miscarriages.
-Congenital abnormalities due to segregation at meiosis, resulting in unbalanced gametes.
• Identified as exchange of chromosomal material between non-homologous chromosomes.
• Break points can be in short/long arm - generally in non-transcribing DNA.
• Therefore little, if any, phenotypic effect.

Robertsonian translocations
• Affects acrocentric chromosomes 13, 14, 15, 21 and 22.
• Associated with recurring miscarriage and impaired spermatogenesis.
• Mal-segregation can give rise to Down's if 21 involved or Patau's if 13 involved.

Inversions
• Paracentric gametes - normal/inversion/dicentric/acentric.
• Pericentric gametes normal, inversion, duplication/deletion.
• In large pericentric inversions, duplicated and deleted segments very small therefore, newborns may survive.

Haematological malignancies - acquired disorders
• Clonal expansion of neoplastic cells derived from (or resembling) normal haematological cells.
• In general, leukaemias and lymphomas classified according to stage of normal haematopoiesis at which cells appear to be blocked.

Bone marrow samples
• Bone marrow obtained via iliac crest puncture by haematologist.
• Reasons for referral include:
-Confirmation of diagnosis for chronic myeloid leukaemia.
-Acute myeloid leukaemia (M2, M3, M4).
• Indication of prognosis, particularly in childhood ALL.

CPC On Genetic Disease

2007-03-10T12:25:00.002Z

16.2.07

Case 1
• Male aged 24.
• Family history of colon cancer.
• Been on screening since aged 10.
• Now colectomy.

Familial adenomatous polypoposis (FAP)
• Autosomal dominant.
• APC gene - tumour suppressor gene.
• Dominant inheritance, but woks as recessive gene.
• Compare RB gene (retinoblastoma).
• Clinically: polyps in large intestine increased during childhood.
• Malignancy inevitable by late 20s.

Normal
APC loss/mutation
Metaplastic polyp
Loss of DNA methylation
Adenoma
Ras mutation (12p)
Adenoma
Loss of DCC (18q)
Late adenoma
Loss of p53
Carcinoma

Other tumour suppressor genes
• NF-1: neuroblastoma.
• NF-2: Schwannoma, meningioma.
• RB: retinoblastoma, osteosarcoma.
• p53: Li Fraumeni syndrome.
• WT-1: Wilms tumour (renal).
• BRCA-1, 2: Breast, ovary carcinoma.

Case 2
• Female, aged 42, well.
• Patient's uncle died from ischaemic heart disease aged 62.
• Sudden death, therefore, autopsy.
• Liver looked nodular.
• Histology taken.

Next…
• Patient has liver investigations and biopsy.
• LFTs normal.
• Ferritin high, serum iron high.

Autosomal recessive
• Genetic Haemochromatosis.
• Example of "founder" gene mutation (800AD, Celtic population).
• Iron overload due to increased absorption.
• May exceed 50g total (normal <6g).
• Commoner/earlier in men (no blood loss).
• Carrier 1:9 in Northern Europe, homozygotes 1:220 (but penetrance only ~20%).

Haemochromatosis
• Iron in toxic excess (catalyses free radicals).
• Results in:
-Cirrhosis.
-Pancreatic fibrosis.
-Cardiomyopathy.
-Tumours, especially hepatocellular carcinoma.

Other founder mutations - all recessive
Mutation Heterozygote resists
CF Diarrhoea
Sickle cell Malaria
FV Leiden (clotting) Sepsis
ALDH2 (alcohol) Alcoholism (?)
Lactose tolerance Allows milk use
GHB2 (deafness, Middle East) Unknown

Case 3
• Ghanaian (black) male aged 23.
• Episodes of severe abdominal and joint pain.
• Bad enough to need opiates.
• Last attack precipitated by bronchitis.

Sickle cell anaemia
• Recessive (autosomal).
• Point mutation at position 6 of beta globin chain.
• West Africa.
• Homozygote - crises caused by hypoxia ± infection.
• Autosplenectomy.
• Danger from hypoxia.
• Danger from infection, especially pneumonia.
• Joint damage from sickle crises.

Case 4
• Male aged 37 with family history of early cardiac death.
• Father died aged 42.
• Uncle died aged 44.
• Patient overweight (BMI = 34).
• And has xanthelasmata.

Investigations
• Cholesterol 12 mmol.
• LDL 8 mmol.
• FBC and clotting normal.
• U+Es and LFTs normal.

Familial hypercholesterolaemia
• Heterozygote 1:500.
• Typical cholesterol >7.5 mmol.
• Risk of early heart disease and stroke.
• Homozygote much rarer, but more severely affected.
• Cholesterol can be as high as 30!

Case 5
• Male patient aged 41 develops heart failure.
• Tall, thin, blue sclerae, long spidery fingers, pectus excavatus, high arched palate.
• Valve replacement.
• Died suddenly 2 years later.

Marfan's syndrome
• Incidence 1:5000.
• 75% cases familial autosomal dominant.
• Remainder sporadic (new mutation).
• Defect in fibrillin-1: abnormal form due to missense mutations.
• Tall with long gingers and toes.
• Relatively shorter upper body and long legs.
• Double-jointed digits.
• Eye.
• CVS.
• Sudden death from CVS causes.

X-linked recessive: fragile X
• Causes learning difficulties.
• Next commonest after Down's.
• IQ 20-60. Long face, large jaw and ears.
• Macro-orchidism.
• ~20% carrier males normal, but can transmit disorder.
• ~50% carrier females not affected.
• FMR-1 gene at Xq27.3 has CGG repeats in 5' untranslated region.
• Normally 10-55 repeats (average 29).
• Transmitter males pass on permutation without much amplification.
• Carrier females pass on dramatically amplified mutation.
• Amplification probably occurs in oogenesis, but not spermatogenesis.

Future prospects
• Better understanding of diseases (known genetic and postulated environmental), with application of Human Genome Project.
• Genetic tailoring of drug therapy.
• Common drugs like statins and anti-inflammatories may benefit.
• Tailored cancer treatment.

Pathology Of Genetic Disease

2007-03-10T12:25:00.001Z

16.2.07

Developments
• Human Genome Project.
-Polymorphisms.
-0.1% (3mBp) variable.
-Imprinting ?role.

Congenital and genetic
• Congenital: existing at or before birth - may not become apparent until later.
• Genetic: inherited.

Genetic diseases
• >1000 known to affect humans.
• Diseases with at least some genetic component will affect 2/3 of population during lifetime.

Mutations
• Different scales.
-Whole chromosome gain/loss.
§Monosomy/trisomy.
+Mostly not transmitted.
-Chromosome rearrangement.
-Gene level (submicroscopic).

Cytogenic autosomal disorders
• Trisomies:
-Down's syndrome (trisomy 21).
§Average incidence 1/700 (1/25 if mother >45 years).
§95% cases maternal origin.
§40% patients have congenital heart disease.
§Rate of acute leukaemia increases 10-20X.
§Many get Alzheimer's after age 40 years.
-Edwards (trisomy 18) and Patau's (trisomy 13) rarer.

Sex chromosome disorders
• Two most common:
-Kilnefelter's (47, XXY/variants), 1:500 male.
§Hypogonadism, infertility.
§Mild learning difficulties (not all).
§Effect of extra X probably mitigated by lyonisation.
-Turners (45, X), 1:2000 female births.
§Many (?all) mosaics with XX, XY, XXX etc.
§Hypogonadal, short stature, skin webs.
§IQ often in normal range.

Mutations
• Gene level.
-Deletion (partial/complete).
-Point mutation (single base).
-Insertions/deletions → frame shift.
§Base pair gain/loss.
-Mutations in promoter/enhancer regions.
§Non-coding, but can interfere with transcription.
§Trinucleotide repeats (usually C and G bases).
-Mutation/deletions of MMR genes (HNPCC).

Mendelian disorders: autosomal dominant
• Affect 50% children.
• Parent often affected.
• May be late onset of effect.
• Variable penetrance (incidence).
• Variable expressivity (effect).
• Enzymes not usually involved because ~50% remains (other copy).
• Loss of function due to:
-Regulatory proteins involved in feedback.
-Key structural proteins.
• Gain of function e.g. overexpression.
• Colon: FAP.
• Chemistry:
-Acute intermittent Porphyria.
-Familial hypercholesterolaemia.
• Bones:
-Marfan.
Ehlers-Danlos.
-Osteogenesis imperfecta.
-Achondroplasia.
• Renal: polycystic kidneys.
• Blood:
-Hereditary spherocytosis.
-Von Willebrand's.
• CNS:
-Huntington's disease.
-Von Recklinghausen.
-Myotonic dystrophy.
-Tuberous sclerosis.

Mendelian disorders: autosomal recessive
• Everybody carries 5-8 recessive harmful genes.
• Parents phenotypically normal, but 25% siblings affected.
• Usually complete penetrance.
• Early onset.
• Blood:
-Sickle cell.
-Thalassaemias.
• Bone:
-Some Ehlers-Danlos.
-Alkaptomina.
• Endocrine: congenital adrenal hyperplasia.
• CNS.
• Chemistry:
-CF.
-PKU.
-Galactosaemia.
-Homocystinuria.
-Lysosomal storage disorders.
-Alpha-1-anti-trypsin deficiency.
-Wilson's disease.
-Haemochromatosis.
-Glycogen storage diseases.

Sex chromosomes
• Y chromosome has:
-Genes related to spermatogenesis (with internal copies).
-A few genes homologous to those on X, but no syndromes known from these.
• X chromosome (in female) is randomly inactivated (lyonisation) - mosaic state.

X-linked (recessive) disorders
• Males affected:
-Females may be partly affected due to lyonisation.
-Males described as hemizygous as no paired Y-chromosome gene generally exists.
-Affected males transmit disorder to daughters as carriers, but not to sons.
• Chemistry:
-Diabetes insipidus.
-Lesch-Nyhan (uric acid).
• Muscle: Duchenne's.
• Blood:
-Haemophilia A and B.
-Chronic granulomatous disease.
-G-6-PD deficiency.
-Agammaglobulinaemia.
-Wiskott-Aldrich (immunodeficiency).
• CNS: fragile X syndrome.

Single gene disorders: effects
• Enzyme defects:
-Substrate build-up.
§Mucopolysaccharidoses.
§Lysosomal storage diseases.
-Lack of product.
§Albinism.
§A-1-A-T deficiency.
• Structural alterations in other proteins - haemoglobinopathies - sickle cell anaemia (not thalassaemias).
• Altered reaction to drugs.
• Defects in membrane receptors.

Multifactorial genetic disorders
• Interaction with environment likely.
• Could be 7-10 genes involved.
• Congenital malformations easily observable model.
-Cleft lip/palate.
-Heart.
• IHD.
• Hypertension.
• Diabetes mellitus (especially type II).
• Pyloric stenosis.
• Gout.

Non-Mendelian disorders
• Triplet repeats: fragile X.
• Mitochondrial genes:
-Maternal inheritance.
-37 genes (24 translating and 13 code for metabolic enzymes).
-Several conditions:
§Leber optic neuropathy.
§Mitochondrial myopathy.

Diagnosis, Risks, Inheritance And Genetic Testing

2007-03-10T12:24:00.000Z

12.2.07

Making referral to clinical genetics
• Positive family history, ?syndrome.
• Worried, when asked, planning children.
• Tell family about referral.
• Diagnosis, family history, age, investigations so far.
• What family know already etc.

Huntington's disease
• Autosomal dominant, 50% risk of transmission.
• Variable age of (adult) onset: 30s-50s.
• Anticipation, especially from father.
• Gene (triplet repeat) on chromosome 4p.
• Involuntary movements, tremor, chorea.
• Change of personality, drive.
• Behavioural changes.
• Psychiatric symptoms.

Diagnostic and predictive tests
• In presence of symptoms.
• Unaffected, but wants to know.
• Testing of foetus during pregnancy (at-risk parent knows their status).
• Excluding risk of Huntington's disease in foetus (at-risk parent does not want to know their status).

Issues in predictive genetic testing
• Testing asymptomatic for late-onset conditions.
• To know or not to know?
• Is there useful intervention?
• Possible harmful psychological effects.
• Insurance and employment issues.
• Does not predict age of onset/severity etc.

X (sex)-linked inheritance
• Women = carriers.
• Men affected (knight's move).
• No male-to-male transmission.

What can the Human Genome Project deliver?
• Genetic diagnosis, understanding process.
• Novel treatments, gene therapy.
• Miscarriage, infertility, organ transplantation.
• Dementia, heart disease, cancer.
• Genetically-produced drugs, gene therapy.
• Stem cells for transplantation.
• Information, ethical and practical dilemmas.

• SNPs - single-nucleotide polymorphisms.
• UK Biobank.

Module 2.10

2007-03-10T12:23:00.000Z

A Family Slowly Going Off Their Legs.
12.2.07 - 23.2.07.

The Case Of A Patient Undergoing Surgery

2007-03-10T12:21:00.000Z

5.2.07

Preoperative anaesthetic visit
• Explain all details of perioperative period.
• Allay anxiety.
• Answer queries.
• Check appropriate investigations have been done.
• Prescribe premedication.
• Explain procedure.
• Detail possible methods of postoperative analgesia e.g. PCA, epidural, spinal.
• Explain risks.
• Explain post-operative procedure.

Preoperative anaesthetic assessment
• Any previous anaesthetic?
• Allergic reaction?
• Awareness.
• Anxiety.

Drug therapies
• Should they be continued?
• Is it optimal?
• Any drug allergies?

Anatomy of airway
• Is it abnormal?
• Any pathology?
• Can patient open mouth?
• Any airway infection?
• Check teeth.

Preoperative preparation - indications for:
• Physiotherapy.
• Anti-embolism stockings.
• Heparin.

Preoperative investigations
• Which of these does she need?
• FBC, U+Es, Ca, glucose.
• Cross-match.
• CXR.
• ECG.
• Lung function tests.
• Blood gas analysis.

Premedication
• Allay anxiety.
• Relieve pain.
• Anti-sialogogue.
• Appropriate for surgery e.g. drying agent for surgery on airway.

Premedicants
• Anxiolytics: benzodiazepines, trimeprazine.
• Analgesics: oral e.g. NSAIDs, paracetemol; parenteral e.g. opiates, NSAIDs.
• Anticholinergics: atropine.
• Antiemetics.

Preparation for theatre
• Starve:
-4 hours: no fluid.
-6 hours: no solid food.
• Consent, correct side.
• No artificial teeth, hairgrips, jewellery, make-up.
• Empty bowel and bladder.

Immediate postoperative care recovery room
• Adequate oxygenation (any facial deformities?).
• Adequate pain relief.
• Adequate fluid therapy.

Postoperative pain
• Minor surgery, day case.
-Simple oral analgesia e.g. paracetemol, Dihydrocodeine.
• Intermediate surgery.
-NSAIDs, IM opiates.

Major surgery: postoperative pain
• IV opiates: continuous infusion patient-controlled analgesia (PCA).
• Epidural analgesics: local anaesthetic agents e.g. lignocaine, bupivicaine; opioids analgesics e.g. diamorphine, morphine, fentanyl - must be preservative-free.
• Local nerve blocks e.g. intercostals nerve blocks for thoracic surgery, 3-in-1 block for hip surgery.
• Spinal analgesia for lower abdominal and lower limb surgery.

Postoperative care - risks of:
• Chest infection (is she a smoker?).
• Appropriate antibiotic cover.
• DVT, PE (any risk factors?).
• MI.

Postoperative chest infection
• Which is most common organism to cause it?
• Is there risk of transmission?
• Other therapies.
• Physiotherapy.
• Nebulisation.

Waiting Lists And Discharges - Does The NHS Need More Beds?

2007-03-10T12:20:00.000Z

5.2.07

1997: impending crisis
• 1,132,200 patients on waiting lists for hospital admission.
• 30,000 patients waiting for >1 year.

What causes waiting lists?
• Under-funding.
• Rationing.
• Inefficiency.
• Vested interests.

Waiting pools, not lists
• Treatment pool.
• Assessment pool.
• Not referred pool.

1997 political focus on waiting lists.

Cancer plan 1997
• Fast track referrals.
• Maximum 2-week wait.
-Breast cancer by April 1999.
-All other cancers by 2001.

March 2000
• 100,000 reduction achieved.
• 18-month waits virtually eliminated.
• 50,000 waiting 12 months.
• 130,000 waiting >26 weeks.

NHS plan 2000
• Outpatient:
-Maximum wait reduced from 6 to 3 months.
-Average wait 5 months.
• Inpatient:
-Maximum wait reduced from 18 to 6 months.
-Average wait 5 months.

National Beds Enquiry 2000
• Numbers and distribution of beds.
• Factors determining usage of beds.
• 66% beds occupied by patients >65.
• Traditional role of NHS:
-Managing life's incidents.
-Acute care.
• Ageing population:
-Increased chronic disease.
-Proactive and ongoing care.

The response
• Accelerating discharge:
-Reform of hospital organisation.
-Support in the community.
• Reducing admissions.
-Alternative treatments.
-Support in the community.

• Absence of alternatives to acute care contributory factor to all categories of delay.

Delayed discharge from hospital
• Symptom and cause of:
-Poor bed management.
-Failure of communication between health and social care.

Problems with hospital discharge
• Delayed.
• Occurs too soon.
• Poorly-managed from patient/carer perspective.
• Transfer to unsafe environments.

Causes of delayed discharge
• Internal hospital factors:
-Timing of ward rounds.
-Waits for results.
-Delay in home assessment.
-Organisation of medication.
-Availability of transport.
• Coordination issues:
-Health services.
-Social care services.
-Other community services.
• Capacity and resource issues:
-Availability of rehabilitation places.
-Placement difficulty with care homes.
-Availability of home care provider.
• Patient/carer involvement:
-Failure to involve in decision-making.
-Limited choice of care options.

Improving discharge performance
• Discharge = process, not isolated event.
• Transfer from hospital to appropriate setting needs careful planning.
• Discharge planning should start before elective admissions and ASAP after emergency admissions.
• Patients and carers should be involved at all stages.

Improving services for vulnerable people

Intermediate care
• Range of integrated services to:
-Promote faster recovery from illness.
-Support timely discharge.
• In Liverpool:
-Emergency Response Team (ERT).
-Intermediate care team.
-ACTRITE (A+E assessment of COPD patients).
-Tracker nurses.
-Orthopaedic rehabilitation at home.

Patient journey through illness
• Many people fear experience of hospitalisation and loss of autonomy.
• Want to return to living normal lives ASAP: every effort should be made to help them do so.
• Acute hospitals should only be used for delivery of services that cannot be provided as effectively in home/social setting/community

Having An Operation CPC

2007-02-03T17:14:00.001Z

2.2.07

Pre-op work-up
• Haematology.
• Biochemistry.
• CXR/ECG.
• Special cases.
-Drug history, especially steroids.
-DM.

Anaemia
• Haemorrhage.
• Iron deficiency.
• Megaloblastic (including pernicious anaemia).

Blood transfusion
• When to give it.
• Group and save.
• Emergency situation.
• Cross-match.
• Risks.
-Reactions.
-Infections.
• Auto-transfusion.

Wound infections
• Cellulitis (Strep.)
• Abscess (Staph.)
• Commonest organisms.

Bacterial damage
• Virulence increased with population density.
-Adherence.

Adherence
• Adhesins.
-Fimbriae/pili on Gram negative bacteria.

Invasion
• M. tuberculosis.
-Opsonised with C3.
-Invades macrophages via C36 receptor.
-Phagosome/lysosome fusion blocked.
• Gram-negative bacteria.
-Inject "transmitter" proteins into cell that rearrange structure and facilitate entry.

Toxins
• Exotoxins.
-Enzymes.
§Protease.
§Hyaluronidase.
§Coagulase.
-Signal blockers.
§Receptor binding part + enzyme.
-Neurotoxins.
§Botulinum, tetanus.
-Superantigens.
§Toxic shock syndrome.
~Stimulate many T cells → cytokines.
• Endotoxins.
-Lipopolysaccharides.
§Constant part and variable ("O") part (O157).
§Small doses enhance immune response.
§Large doses overwhelm it e.g. sepsis.
~DIC.
~ARDS.
~Cytokine release (IL-1, IL-2, TNF-α).

Lung infections
• Pneumonia.
• Organisms.
-Pneumococcus.
-Haemophilus.
-Klebsiella.
-Legionella.
-Opportunists.
-Fungi.
-Viral.

Wound Healing

2007-02-03T17:14:00.000Z

2.2.07

Terms
• Resolution e.g. lobar pneumonia.
• Repair.
• Regeneration.
• Organisation.
• Replacement.

Regeneration
• Labile cells.
-Epithelia, blood cells.
• Stable cells.
-Organs with "no" stem cells e.g. liver.
• Permanent cells.
-Neurones in CNS.
-Muscle (skeletal and cardiac).
• Role of stem cells in regeneration.

Regeneration of stable cells
• Mitogenic signals.
-Autocrine.
-Paracrine.
-Endocrine.
• Receptors.
• Signal transduction.
• DNA-binding proteins.
• Framework required.

Organisation
• Exudate.
• Fibroblasts and blood vessels.
• Collagenous scar.
• E.g.
-Peritoneal adhesions.
-Pericarditis.
-Pulmonary fibrosis.

Wound healing
• Primary intention.
-Clean surgical wound firmly apposed.
• Secondary intention.
-Large, denuded wound e.g. abrasion, burn.

Events in wound
• Haemorrhage → clotting.
-Platelets.
-Fibrin(ogen) and fibronectin.
• Epidermis.
-Cells migrate over wound.
§Marginal keratinocytes interact with fibronectin.
§Cells proliferate (start 12 hours after wounding).

Events in wound - dermis
• Neutrophils → wound (12-24 hours).
• Macrophages → wound (24 hours+).
-Demolition.
-Angiogenesis.
§Vascular buds; leaky, fragile capillaries.
§Granulation tissue.
-Stimulation of fibroblasts.
§VEGF increases permeability and leakage.
§Macrophages produce PDGF, TGF-β and FGF.
-Collagen maturation.

Growth factors
• EGF (epidermal).
-Also stimulates mesenchyme.
-Mouth and GIT, but not skin wounds.
• PDGF (platelet-derived).
-Mitogenic, chemoattractant (chemotaxis).
• FGF (basic fibroblast).
-Angiogenesis.
-Cell migration.
-Haemopoiesis.
-Muscle and lung maturation.
• VEGF (vascular endothelial).
-Vasculogenesis in embryo.
-Angiogenesis (tumours, healing).
-Varieties: -C acts on lymphatics.
• TGF-α (transforming).
-Homology to EGF - found in wounds.
• TGF-β.

Cytokines
• Produced by inflammatory cells.
-IL-1.
§Stimulates fibroblasts to divide, synthesise collagen and also produce collagenase.
-TNF-α.
§Tumour cell killing.
§Wasting.
§Inflammatory diseases/conditions.
§Stimulates new blood vessels.

Collagen and extracellular matrix
• ECM.
-Collagens and elastins.
-Adhesives: fibronectin, laminin.
-Proteoglycans and hyeluronan.
• Collagen.
-14 types.
§Types 1-3 fibrillar.
§Type 4 in basement membrane.

Wound strength regained
• 10% at 1 week (stitches out).
• Increases to 70% by 5 weeks and plateaus at ~ 80%.
• GIT anastomosis 90% by 8 days.

Large wounds
• Secondary intention.
-More granulation tissue.
-Wound contraction.
§Myofibroblast (contains actin, but no myosin).
§Fibronectin molecules bridge myofibroblasts and collagen fibres.

Factors limiting wound healing
• Systemic.
-Lack of:
§Protein.
§Vitamins (A, C).
§Zinc.
-Steroids.
-Age (?)
-Diabetes.
• Local.
-Lack of immobilisation.
-Foreign body/infection.
-Blood supply (including venous drainage) e.g. leg ulcers.
-Poor oxygenation.
• Complication: keloid scar.

Healing of bone
• Fracture → haemorrhage.
-Inflammation.
-Necrosis locally.
-Granulation tissue.
• Provisional callus.
-Woven bone with cartilage islands.
• External callus.
• Remodelling.
-Possible sources of failure.

Module 2.09

2007-02-03T17:13:00.000Z

Having An Operation.
29.1.07 - 9.2.07.

The Immunology Of Rheumatoid Arthritis

2007-02-03T17:10:00.000Z

22.1.07

What is RA?
• Chronic and inflammatory disease of some joints and often other tissues.
• Mechanism(s) leading to activation of immune system unknown - AUTOIMMUNE DISEASE.

Conventional view of autoimmune disease
• Autoimmunity: abnormal immune response that destroys otherwise normal tissue.
• Abnormal activation of offending immune cells (very often CD4+ T lymphocytes).

Function of immune system
• Recognise changes (due to infections/malignant transformation) by constantly monitoring all cells in body.
• When change is detected, attract the necessary responding cells into close vicinity.
• Eliminate changed cells and remove the debris.
• Terminate the response (by killing most responding cells).
• Provide some memory in case same change occurs again.

Island empire analogy
• Imagine body = island.
• Immune system acts as border patrol, police and army.
• Role:
-Not to let anybody in.
-Eliminate all defectors.

Divisions of law enforcement
Pest control officers (granulocytes)
• Lots, everywhere.
• Short-lived.

Community patrol officers: professional antigen-presenting cells, dendritic cells
• Present everywhere, but numbers higher at sites where invasion from outside likely e.g. skin, gut, liver.
• Get despatched to area where they remain stationed for long time.
• Listen, but do not talk.
• Good at picking up antigens, but not presenting.
• Once older. Go back to base to report.

Commanding officers: CD4+ T"helper" lymphocytes
• Lots (CD4:CD8 = 2:1).
• Have been drilled in thymus: if community patrol officer reports "A," give specific order "B."
• No space for individual decision-making.
• TCR expression establishes antigen-specificity - cytokine response profile predetermined.
• Bit of confusion in differences in cytokine production following same antigenic stimulus, TH1 vs TH2 cells.

Cytotoxic (CD8+) lymphocytes: foot soldiers of the empire
• Have been trained at same camp (thymus) as commanding officers.
• Can see enemy (have TCR for antigen recognition).

Chemical response team: B lymphocytes (and complement)
• Relatively few.
• While foot soldiers walk up to enemy and kill it in close quarters, chemical response team concocts poison.

Monocytes/macrophages
• Bit of Jack-of-all-trades.
• Eat pests, just like pest control (direct Phagocytosis).
• Eat unwanted citizens (ADCC, apoptotic cells).

What is autoimmunity?
• Revolt (citizens fail to behave and they get punished for it)?
• Reconnaissance failure (community officers misinform commanders)?
• Have commanders gone beserk (abnormal T cell activation)?
• Is it something else?

Evidence for innocence of synovial cells
• Transplanted arthritic synovial tissue in immunocompromised host: disease stays active (for how long, though?)
• If you eliminate inflammatory cells: synovium returns to normal.
• Animal experiments: can transfer inflammatory arthritis.

Prosecution's view
• Take immunocompromised host.
• Transplant normal synovium at one site, arthritic synovium at another distinct site, and observe.
• Aggressive, proliferating synovial cells (not lymphocytes) migrate to healthy synovium.
• These cells behave like metastatic tumours (in inflammatory arthritis, same enzymatic system is active that facilitates metastases formation in cancer).

Further evidence for guilt of synovial cells
• Establish monolayer of cells from synovial fibroblasts.
• Place on top of patient's own lymphocytes.
• Inflammatory foci will develop in well-defined areas.
• Mark these areas.
• Increasing evidence that synovial cells show significant changes in RA.
• However, whether defects described to date cause initiation of RA remains to be seen.

Principals of DC antigen presentation
• Origins of DC:
-Monocytic.
-Myeloid.
-Plasmocytoid.
• Common feature: maturation.
-Immature cells pick up antigens.
-mature cells present them.
• Question: when is DC signal activating and when is it tolerogenic?

Extended functionality of B cells
• "Chemical response team" view simplistic: these guys undergo significant maturation during life span and almost think sometimes…
• Resting/immature B cells have antigen-specific receptors, but are very inactive.
• When activated by commanding officers (in right cytokine environment provided by CD4+ T cells), B lymphocytes:
-"Fine tune" antigen receptors (somatic hypermutation).
-Start expressing.

Story of three mice - does this work in humans?
• In some RA patients, elimination of active mature B cells with anti-CD20 antibody leads to long-lasting disease remission.
• Unfortunately, CD20 not unique B cell marker.
• Some T cells and dendritic cells also express it.

Role of commanding officers
• A lot around joints (but not quite as many as some T cell immunologists would like you to believe).
• Do look nasty…
• …And remember animal experiements.

Why CD4+ T cells could be less important than originally thought
• Almost all of these cells of memory phenotype.
• Would be recruited (rather than non-specifically) to any inflammation site, just in case you need them.
• Do not proliferate much, do not produce IL-2 much - if anything, are a bit depressed.
• Eliminating them does not bring spectacular success in therapy.

Question
• Why do these memory T cells end up in the joints?
• Answer: don't know.
• If we did, could prevent and cure RA.
• It is something that is very difficult to study.

Is RA result of abnormal T cell regulation?
• In healthy individuals, there are a number of safety mechanisms that switch off ongoing immune response.
• Many of these seem either defective/inefficient in RA.

Regulatory pathways
• Activation-induced cell death.
• CD4+, CD25+ regulatory T cells.
-Tolerise activated T cells via direct cells contact.
• Type II regulatory T cells.
-Produce tolerogenic cytokines.
• NKT cells (CD1d restricted, Vα24+ T cells).
-Induce tolerance via IL-4, IL-12 production.
-Recent evidence indicates interaction with DCs.
• NK cells (CD158-, CD94bright NK cells).
-Kill immature DCs affecting antigen presentation.

Final word of cytokines
• "Words" by which members of immune system communicate with each other.
• Language not that complex (compared to human verbal communication).
• Some of these "words used very often - some cytokines involved in multiple, vital regulatory pathways.

Autoimmune Disease

2007-02-03T17:09:00.000Z

19.1.07

Autoimmunity
• Central tolerance.
-Thymus (T-cells).
-Bone marrow (B-cells).
-Clonal deletion of self-reacting cells.
-Come are missed - present in normal health.
• Peripheral tolerance.
-Regulatory CD4+ T-cells [CD=cluster designation - apply to some membrane antigens - ~200, but low numbers tend to be discovered first.]
-Anergy of lymphocytes (irreversible).
-Clonal deletion (activation - induced cell death).
-Antigen hiding.

T-regulator cells
• CD4+, CD25+, foxp3++.
• Suppress autoreactive T-helpers permanently.
• Outcompete other T-cells for APC binding.
• Inactivates antigen-presenting cell (prevents stimulation of other T-cells).
• Binds onto APC adjacent to T-cell and inhibits it directly.

Autoimmunity
• Loss of tolerance.
-Genetic factors (HLA, AIRE, Fas, CTLA-4).
-Infection.
§General factors.
~Cytokines.
~Release of damaged proteins.
~Molecular mimicry.
§Homologous sequences e.g. strep.
-Hidden sites: special effects in eye, brain, testes.
• Generalised.
-Connective tissue disorders.
• Single/restricted organ damage.
-Hashimoto's.
-Pernicious anaemia.
-Goodpasture's.
-etc.

Connective tissue disorders
• Rheumatoid arthritis.
• Systemic lupus erythematosus (SLE).
• Scleroderma.
• Etc.

Rheumatoid arthritis
Overview
• Systemic disease, mainly involving joints, but also:
-Blood vessels.
-Skin.
-Muscles.
-Lungs.
-Heart.
• Incidence ~1%, mainly F 40-70 (F:M ratio = 3:1).

Joints
• Stages.
-Villous synovitis.
-Vascularises.
-Fibrinous exudates (rice bodies and pmn).
-Osteoclastic activity increased.
§Erosions, cysts, juxta-articular osteoporosis.
-Pannus formation.
§Synovium and granulation tissue.
§Covers and erodes cartilage.
§Bridging and anklosis.

Other sites
• Skin.
-Rheumatoid nodules (elbow, head, back).
§Necrosis and palisaded macrophages.
• Blood vessels.
-Vasculitis.
§Neuropathy and gangrene.

Pathogenesis
• Immunology: excessive CD4+ cells, but unknown trigger (??Proteus).
• Twin concordance - genetic, but not simples.
• No clear HLA linkage.
• Immune complex deposition.
• Excessive TNF and IL-1 from macrophages and synovial cells.

Clinical
• Onset.
-Often slow, with:
§Malaise.
§Fatigue.
§Generalised pain in limbs.
-Small joints involved first.
§Hands and feet, tends to progress centrally.
• Hot, swollen joints.
-Develop deformities later.
• Painful after resting.
• Remitting, relapsing disease.
-Baker's cyst.
• X-ray findings.
-Erosions, narrowed joint, osteoporosis.
• Tests - none very specific/sensitive.
-Rheumatoid factor.
§IgM anti IgG-Fc.
-ESR.
• Diagnosis in presence of more than three of the following:
-Morning stiffness.
-More than two arthritic joint groups.
-Hands involved.
-Symmetrical involvement.
-X-ray changes.
-Rheumatoid nodules.
-Rheumatoid factor.

SLE
• Most protean (multisystem) of them all.
• Chronic remitting relapsing disease, often febrile, characterised by injury to skin, joints, kidney, serosal membranes.
• Incidence: 1/2500, F:M ratio = 9:1, age 10-30 commonest (1:700 young women).

Clinical
• May start acutely.
-Sudden onset.
-High fever.
• Red raised (malar) rash frequently present.
• Frequent, recurrent pleurisy.

Genetics
• Twins (20% vs 2%).
• HLA (A1, A8, DR-2, DR-3).
• Inherited complement deficiency (C1q, C2, C4 in 6%).
• C1q needed to clear apoptotic cells.

Environmental
• Drugs.
-Penicillamine.
-Procainamide.
-Hydrallazine.
• UV light.
-?immunosuppressive role.

Hormonal
• Sex hormones.
-Much commoner in females.
-SLE may flare during:
§Pregnancy.
§Menstruation.

Serology
• Antinuclear antibodies:
-D-DNA.
-S-DNA.
-RNA.
-RNA protein.
-Histone.
-Nucleoli.
• Anti-blood cell antibodies: immune complexes.
• Patients affected in %:
-Fever 84%.
-Skin rash 72%.
-Renal 60%.
-Pleural 50%.
-Heart 50%.
-CNS 25%.
• Remitting fever with crises etc.
• Criteria:
-Renal damage.
-CNS signs (seizures, psychosis etc.)
-Blood cytopenias.
-Autoantibodies (including antiphospholipid).

Anti-phospholipid antibodies
• Actually directed against plasma proteins complexed to somewhere else.
• May give false and WR (cardiolipin).
• Lupus anticoagulant in vitro, but…
• Procoagulant in vivo.
-DVT.
-Repeated miscarriage.
-Cerebral ischaemia.

Scleroderma
• Main characteristic: excessive fibrosis throughout body.
• Skin, GIT, kidney, heart, muscle, lungs.
• F:M ratio = 2-5:1.
• Immunology: activated CD4+ cells in skin of many patients.
• Characteristic antibodies: Scl 70, anti-centromere.
• Hypotheses:
1. Autoimmune trigger for collagen synthesis.
2. Abnormal collagen metabolism.
3. Microvascular abnormality.
• Clinical.
-Thickening of hand ± Raynaud's.
-Articular pain.
-Dysphagia.
-Pain.
-Obstruction.
-Malabsorption.
-Renal damage.
-Hypertension.
-Diffuse fibrosis.
• "CREST": benign variant: calcinosis, Raynaud's, oesophageal fibrosis, sclerodactyly.

Polymyositis/dermatomyositis
• Myopathy and weakness due to degenration of groups of muscle fibre, with inflammation.
• Types.
-Typical adult myositis, dermatomyositis.
-Malignant associated (12%).
-Childhood.
-Associated with other connective tissue disease.
• Immunology:
-Some antinuclear antibody, possibly specific.
-Childhood type features immune complexes.
• Clinical.
-Initially arm, then proximal leg.
-Later, extends to limb girdles, neck, pharynx, intercostals and diaphragm.
-Initial oedema, then atrophy.

Sjögren's disease
• Primary: sicca syndrome.
• Secondary: with other autoimmune diseases.
• Decrease in salivary and lachrymal secretions due to lymphocytic infiltrate and fibrosis.
• Immunology:
-Some B-cells.
-75% have RF.
-65% have antinuclear factor.
-LE test positive in 25%.
-Antibody to duct cells, smooth muscle mitochondria, GPC, thyroid.
-SS-A and SS-B antibodies.
-If RA also present, RANA found.
• Clinical.
-Corneal ulceration.
-Oral fissuring and ulceration.
-Dry nose.
-Possible bronchial involvement.
-25% cases involve extraglandular tissues.

The Spectrum Of Arthritis

2007-01-15T19:05:00.000Z

15.1.07

What is arthritis?
• Damage to joints.
• Pain (usually).
• Reduced function - "joint failure."
• Many causes.
• Various treatments - including curative!

Spectrum of arthritis
• Aches and pain very common.
• Not all pains are "arthritis."
• Hundreds of different types of arthritis.
• Average doctor: poor/no training in musculoskeletal disease.
• Importance of early diagnosis (modifiable disease).
• Massive market - pharmaceutical industry!
• One, few or many joints affected.
• Not only joints affected!
• Many different aetiologies.

How to diagnose arthritis
• History.
• Examination.
• Blood tests:
-ESR.
-CRP.
• Imaging:
-X-ray.
-MRI.
-Ultrasound.
-Nuclear medicine.

Aetiology of rheumatic diseases
• Almost all have complex multifactorial aetiology.
• Multiple genes.

Clinical problems
• Single joint (monoarthritis).
• Many joints (polyarthritis).
• A few joints (oligoarthritis).

Aetiology
• Infective (septic).
• Degenerative (osteoarthritis).
• Metabolic (gout).
• Inflammatory (rheumatoid arthritis).

Monoarthritis
• Septic arthritis - can be sexually transmitted.
• Osteoarthritis.
• Crystalarthritis.

Septic arthritis
• Medical emergency.
• Curable.
• Antibiotics IV.
• Lose joint (and limb) if too slow.

Gout
• Podagra.
• Pain "exquisite."
• High serum urate.
• Crystals in joints.
• Profound inflammation.
• Chronic:
-Trophic.
-Renal disease.

Gout: diagnosis
• Serum urate.
• Direct examination for crystals.
• Look at underlying causes.

Pyarthrosis
• Sepsis.
• Crystal synovitis.
• Rheumatoid arthritis (and other inflammation).

Oligoarthritis
• Reactive (HLA-B27-related) arthritis.
• [Psoriatic arthritis.]
• Osteoarthritis.

Reactive arthritis
• As consequence of infection.
• Joint pain.
• Eye problems.
• Ulceration.

Ankylosing spondylitis
• More common in men than women (4-9:1).
• Inflammation in sacroiliac joint, spreading up back.

Psoriatic arthritis
• As result of psoriasis.
• Can be one of worst forms.

Osteoarthritis
• Joint "wearing" inevitable with time.
• When is "wear" "disease"?
• Various patterns: one/many joints.
• Surgery ultimate therapy.
• Lifestyle modification.
• Simple analgesia.
• Disease modification…?

Degenerative disease
• Cardinal features of arthritis on x-ray:
-Joint space narrowing.
-Osteophytes.

Rheumatoid arthritis
• Most common autoimmune disease.
• Not just joints.
• High morbidity.
• High mortality.
• Symmetrical small joint polyarthritis (only synovial).
• Inflammatory.

Module 2.08

2007-01-15T19:04:00.000Z

Pain Taking Over.
15.1.07 - 26.1.07.

Normal And Abnormal Functional Anatomy Of The Lower Limb

2007-01-15T19:03:00.000Z

12.1.07

"Lower limb problems are the most commonly dealt with by physicians."

Physical stress - hip joint
• Trabecular structure of proximal femur generally well-adapted to cope with angle of inclination (normally ~1250 in adult) and bending moments it causes medially.
• However, significant deviations (coxa vara, coxa valga) can lead to reduced mobility and/or fractures of femoral neck.

Iliofemoral ligament prevents hyperextension of hip - strongest ligament in body.

Fracture of neck of femur
• Displacement of distal bone fragment caused by pull of powerful muscles.
• Note in particular: external rotation of leg with foot characteristically pointing laterally.
• Particularly in elderly women, mainly due to thinning of cortical and trabecular bone.
• Avascular necrosis of femoral head is a common complication.

Knee joint
• Articular surface involved in main movement of knee: flexion and extension.
• Articular surfaces of femur represent segment of pulley.
• Cruciate ligaments appear crossed in space.
• Situation important to remember during normal knee movement - also involves some gliding and rotation.
• Cruciate ligaments represented by crossed 4-bar linkage.
• Together with medial and collateral ligaments, intersect at same crossing point - can be maintained in extension and flexion.
• Note: extension in femoral condyles has much greater contact areas as in flexion thus significantly reducing pressure.
• Various structures (e.g. ligaments, menisci and tendons) help stabilise knee joint and dissipate pressure.

The Grandmother's Fall CPC

2007-01-08T19:06:00.000Z

8.1.07

Vitamin D
• Sources:
-From 7-dehydrocholesterol in skin.
§Up to 80% requirements → D3.
-From diet (D2).
§Fish, plants etc.
§Fortified.
• Metabolism:
-Converted to 25(OH)D in liver.
-Then to 1,25(OH)2D in kidney.
-Renal feedback control of 1,25 form to maintain both:
§Itself.
§Ca2+ and PO43- levels.
• Functions:
-More like steroid hormone:
§Absorption of calcium and phosphorus.
§If Ca2+ low, works with parathyroid hormone to increase release.
§Normally required for mineralisation of bones.
§Renal resorption of Ca2+ (?exact mechanism).
§? Differentiation of osteoclasts.

Osteomalacia
• Blood test.
-Reduced Ca2+.
-Mildly reduced PO43-.
-Raised alkaline phosphatase.
• X-ray.
-Bone rarefaction.
-Looser's zones (linear rarefaction) in femoral cortex.

Osteoporosis
• Average 0.7% bone loss per year (normal).
• Peak bone mass.
• Physical activity.
• Ageing effects on osteoblasts.
• Genetic factors (vitamin D receptor affinity).
• Hormonal environment.

Paget's disease of bone
• Blood tests.
-FBC normal for age.
-Marked rise in alkaline phosphatase.
• Features.

Osteopetrosis
• Marble bone disease.
• Inherited osteoclast defect.
• Brittle bones even though dense and heavy.
-Autosomal recessive malignant type.
§Fatal early in life.
-Dominant benign form.
§Fractures in adolescence.

Healing of bone
• Fracture → haemorrhage.
-Inflammation.
-Necrosis locally.
-Granulation tissue - small blood vessels growing into necrosed tissue.
• Provisional callus.
-Woven bone with cartilage islands.
• External callus.
• Remodelling.
-Possible sources of failure.

Sadly, no notes for the second plenary due to sodding comm skills.

Anticoagulation: Drugs For Treatment And Prevention Of Thrombosis

2007-01-05T18:34:00.000Z

5.1.07

Haemostasis and thrombosis
• Haemostasis: complex normal and physiological responses and control mechanisms that ensure limited blood loss following tissue damage and maintain circulating blood in fluid state.
• Thrombosis: abnormal and pathological responses which occur as a consequence of disorders/imbalance of control mechanisms.

Structure of thrombus
• Venous/arterial.
• Endothelial damage.
• Platelet aggregation.
• Activation of clotting cascade.
• Deposition of fibrin.
• Formation of thrombus.

• Subsequent degradation of formed clot.

Diseases caused by thrombus
• MI and unstable angina.
• Arterial thrombosis.
• Thrombotic strokes.
• Venous thrombosis.
• PE.

Coagulation factors
• Factors I - XIII.
• Protein C.
• Protein S.
• Factor IV = Ca2+ ions.
• Factor VI = activated factor V.

Drugs
• Heparins.
• Oral anticoagulants e.g. warfarin.
• Thrombolytics.
• Anti-platelet agents.
• Other drugs.

Heparins
• Naturally occurring mucopolysaccharide.
• Binds and enhances antithrombin III.
• Inhibits clotting factors (IXa, Xa, XIa) and thrombin.
• Dosed parenterally (IV, SC) - adjusted according to APTT.
• Short half-life.
• Low-molecular weight heparins (e.g. dalteparin, enoxaparin) dosed according to body weight and have longer half-life.
• Side effects: bleeding, thrombocytopenia, osteoporosis, hair loss.
• Reversal: protamine (binds to heparin).

Oral anticoagulants
• Warfarin (others, e.g. phenindione, rarely used).
• Inhibits vitamin K-dependent clotting factors (prothrombin II, VII, IX, X, protein C, protein S) - produced in liver.
• Onset of action 48-72 hours (needs to clear factors already formed and circulating).
• Monitored using INR - target value depends on type of clot.

Warfarin
• Metabolised by cytochrome p450 enzymes.
• Protein binding 99%.
• Numerous interactions:
-Potentiate - antibiotics, cimetidine, fluconazole etc. (inhibit p450 or protein displacement).
-Antagonise - anti-TB drugs, anti-epileptics etc.
• Side effects: bleeding, teratogenic.
• Reversal: FFP (rapid), vitamin K.

Thrombolytics
• Streptokinase, Alteplase.
• Activate plasminogen to plasmin.
• Break down established clot.
• Major uses:
-Early MI where reperfusion beneficial.
-Life-threatening PE.
• Contraindications:
-Active peptic ulcer.
-Bleeding disorders.
-Severe hypertension.
-Recent CVA.
-Recent surgery/trauma.
• Side effects: bleeding, allergy (streptokinase).
• Reversal: short half-life, tranexamic acid (inhibits fibrin breakdown).

Anti-platelet drugs
• Oral: aspirin, dipyridamole, clopidogrel.
• Parenteral: prostacyclin.
• Thromboxane A2 and ADP released by activated platelets.
• Thromboxane A2 triggers further platelet aggregation.
• Aspirin inhibits cyclo-oxygenase, which decreases thromboxane A2.
• Clopidogrel inhibits ADP-induced platelet aggregation.
• Side effects: gastric ulceration, hypersensitivity.

Other drugs
• Glycoprotein IIb/IIIa inhibitors:
• Glycoprotein IIb/IIIa:
-Binds VWF (platelet adhesion, carrier for factor VIII).
-Binds fibrin.
• Glycoprotein IIb/IIIa inhibitors block fibrinogen binding to platelets.
• Administered parenterally.
• Expensive! E.g. Abciximab.

Clinical uses
Indication Criteria Treatment Notes
MI Clinical history and ECG Aspirin, fibrinolytics (<6hours) Bleeding, allergy, reperfusion arrhythmias, short door→needle time
Unstable angina, non-STEMI Chest pain
Refractory chest pain Aspirin and heparins ? + GP IIb/IIIa inhibitors
PEs Proven/suspected Heparin followed by warfarin Heparin in pregnancy
DVT Proven/suspected Heparin followed by warfarin Heparin in pregnancy
DVT prophylaxis At risk (dehydration, pre-/post-op, immobility) Low-dose heparin
Prevention of stroke Recurrent TIAs
AF
Valve replacement Aspirin
Warfarin
Warfarin
INR 2-3
INR 3-4

Bone: Structure, Function And Remodelling

2007-01-05T18:31:00.000Z

5.1.07

Functions of bone
• Mechanical:
-Protection.
-Support for other organs.
-System of levers.
• Metabolic function:
-Store for calcium (hypocalcaemia causes tetany).

Joint tissues
Fibrocollagenous
Tendon, ligament, capsule Resists tension Collagen I
Bone Resists compression Collagen I
Mineral
Cartilage Resists compression Collagen II
Proteoglycan
Water

Bone
• Organised in 2 distinct forms:
-Compact bone (cortical bone) - high proportion of bone with few spaces.
-Cancellous/spongy/trabecular bone - low proportion of bone and a lot of space.
• Cancellous bone composed of network of rods and plates called trabeculae.

Bone matrix
• Type I collagen, bone proteoglycan and some non-collagenous proteins: osteocalcin, osteonectin.
• Mineral hydroxyapaptite - a complex calcium phosphate salt.
• Collagen can be laid down into distinct patterns:
-WOVEN BONE, an immature form with random fibre orientation, laid down during rapid growth and fracture repair.
-LAMELLAR BONE, which is composed of successive layers of collagen fibres with distinct orientation.

Structure
• Long bones composed of cylindrical shaft (diaphysis) connected to expanded ends of bone (epiphyses).
• Shell of compact bone surrounds medullary/marrow cavity - site of production of blood cells in immature animals (red marrow), but becomes progressively replaced by inactive yellow marrow, mainly composed of adipose tissue.
• Spongy bone occupies medullary cavity at epiphyses - extends in to metaphysis.

Bone cells
• Osteoblasts:
-Principal function: bone formation.
-Form epithelioid layer on bone surface.
• Osteocytes - osteoblasts engulfed in bone matrix during apposition.
• Lining cells:
-Osteoblasts which have completed phase of synthetic activity.
-Can be reactivated.
• Osteoclasts - large multinucleate cells that "eat" bones.

Osteoid = Bone matrix that has not yet mineralised - mineralisation process still not understood.

Bone remodelling
• Resting.
• Activation.
• Formation - mesenchymal stem cells - osteoblasts.
• Resorption.
• Reversal.

Module 2.07

2007-01-05T18:26:00.000Z

The Grandmother's Fall.
5.1.07 - 12.1.07.

Accessing Electronic Clinical Log

2006-12-14T15:41:00.000Z

17.30.06

Thanks to Rachel for these notes.

Only 1 case needed for formative exams.
Specimen questions available after Christmas on VITAL.

• SPIDER.
• Student records/Medicine/Clinical logbooks.
• Enter core cases.

Other cases
• Select "non-core" from drop-down list.
• Select code.

Case presentation - on clinical placements, in clinical skills OSCEs, post-grad
• History taking.
• Examination.
• Accurate documentation.
• Verbal presentation.

Second Year
• History and examination.
• Basic understanding of management.
• By Fourth Year, you will be expected to discuss/understand all aspects of a case.

OSCE
• Bring 10 core cases - label 1-10.
• 5 minute preparation station:
-Told which presentation.
-Paper provided.
• Use notes as prompt.
• Not necessary to memorise case, but try not to read off sheet.
• Presentation skills assessed.
• 10 minutes to present case.
• Quicker presentation = more time for questions from examiner.
• Bring cases you are familiar with.
• Try to cover a range of conditions.
• Try to find a range of patients.

• PC.
• HPC.
• PMH.
• MxH and allergies.
• FH.
• SH.
• ROS.

Structure
• Examination finding.
• Summary/impression.
• Differential diagnosis.
• Investigations/management.
• Outcome.

Tips
• Comprehensive history.
• Know examination findings.
• Think the case through.
• Present in structured order.
• Be prepared to discuss pathophysiology.

Start
• Relevant information.
• Set the scene.

Passage of time
• Order of presentation and duration of symptoms important.

HPC
• Most questions pertaining to a certain system, but consider others too.

PMH
• List of all medical/surgical events.
• Ask about specific important diseases.

MxH
• Prescribed drugs (current).
• Name.
• Form.
• Dose.
• Frequency.
• Reason.
• Duration.
• OTC.

FH
• All patient's family's medical complaints.
• Don't say "nothing relevant."

ROS
• Expect symptoms relevant to history.
• Don’t ignore others.
• Don't reel off list of things patient doesn't have.

Specialty subjects
• Paediatrics:
-Antenatal/neonatal hx.
-Developmental.
-Immunisation.
• Gynaecology:
-Menstrual etc.

Examination
• Systematic order:
-General inspection.
-Relevant system.
-Other systems.
• Record ALL positive findings, and any relevant negative findings.

Summarising
• Brief - ~3 sentences.

Differential diagnosis
• Start with most likely, then less likely.
• Investigations tailored to help you decide which diagnosis.

Investigation and management
• List simplest initial tests first.
• Should be able to discuss results and their significance.

Common mistakes
• Fibbing.
• Not making sense.
• Using abbreviations (avoid this).
• Missing out important negatives.
• Not finding out about disease process and drugs (classes).
• Not investigating particulars of the case.

Discussion
• Clarifying points in hx.
• Discuss pathophysiology.

Have a good Christmas.

Clinicopathological Conference: Hypertension

2006-12-14T15:40:00.000Z

13.11.06

Take home messages:
• HBP common and usually symptomatic.
• Vast majority of cases primary.
• Treatment to reduce stroke (and IHD) risk.
• Most pts do not take their medications.

Case
• 45-year-old man referred for investigation.
• GP has started screening programme for hypertension:
-200/100 in December;
-190/96 in January;
-190/102 in March.
• Asymptomatic.

What symptoms did you expect?
• Usually none.
• Relationship to headache dubious.
• (Causes of HBP).
• (Results of HBP).

FH
• Father died of stroke aged 55.
• Mother has had 2xMI.
• Elder brother has type II DM.

SH
• Unemployed - ex-car worker.
• Married with children at home.
• Smokes 20/day.
• Drinks 2 pints/day.
• Likes salt.
• No medications.
• NKA.

ROS: causes of HBP?
• Urinary:
-Frequent dysuria?
-Frequent renal angle pain?
-Nocturia?
-Poor stream?
• (Flushing).
• (Polydipsia).

ROS: consequences of HBP?
• Chest pain (angina).
• Dyspnoea/orthopnoea (LVF).
• Transient neurological syndromes:
-Amaurosis fugax.
-Transient hemiparesis.
-Perturbation of consciousness.

ROS: conditions relevant to drugs
• Airways obstruction: β blockers.
• Local urinary problems (prostate in men, stress incontinence in women): loop diuretics.

Examination?
• BP today.
• Consequences of hypertension.
• Other causes of atheroma.
• Causes of hypertension.
• BP = 190/100.

Consequences
• Apex beat - thrusting, but not displaced.
• Heart sounds.
• Fundi.
• (Signs of heart failure).

Other causes of atheroma
• Hyperproteinaemias:
-Xanthomata.
-Xanthalesmata.
-Corneal arcus.

Causes
• Endocrine:
-Phaeochromocytoma.
-Cushings - buffalo hump on back of next with acne and lanego - obesity - peripheral wasting - striae.
-Acromegaly - growth hormone-secreting tumour of anterior pituitary - large tongue, protruding jaw, gappy teeth.
-Conn's - hypokalaemia.
• Metabolic:
-Hypercalcaemia - no physical signs.
• Vascular:
-Coarctation of aorta.
-Renal artery stenosis.
• Renal:
-Polycystic kidneys.
-Features of chronic renal failure.
-Features of nephritic syndrome - vast quantities of albumin in urine - oedema - hypoalbuminaemia.

Case
• Nil on ROS.
• Nil O/E (save wheezy chest).

What tests do you want?
• Urinary.
• Blood.
• Imaging.
• "Special" [har har.]

Urine tests
• Dipstick urinalysis:
-Blood and protein: could be clue to renal pathology.
-Sugar: may be clue to DM.
• MSSU (mid-stream specimen of urine):
-Look for white cells as well as organism growth.
• ALL NORMAL.

Blood tests
• Assess renal function: urea and creatinine.
• (Assess calcium).
• (Assess potassium).
• Fasting blood sugar.
• Fasting lipids - cholesterol = 7.2mmol/L.

Imaging: what do you want to know?
• CXR may help decide about cardiomegaly (but many radiologists think this unnecessary).
• CXR will allow assessment of COAD, and will exclude unsuspected cancer.
• (CXR may pick up Coarctation).
• Renal USS:
-Helps exclude polycystic disease, RAS and hydronephrosis.
-But unless biochemistry abnormal, renal USS often not needed.
• R = 13cm, L = 9cm; ?RAS; what next?

Renal isotope scan with captopril challenge
• Isotope injected IV and excreted.
• Scanning allows rate and extent of excretion of isotope to be determined for each kidney.
• Captopril would reduce perfusion in kidney with RAS.

Lifestyle
• Stop smoking.
• Reduce saturated fat, alcohol, salt.
• Increase oily fish and vegetables.
• Exercise.

Shall we start treatment?
• Trying to decide that patient has SUSTAINED HBP.
• At least 3 recordings, several weeks apart.
• Augmented by 24-hr BP monitor.

Choice of drug
• Little evidence if differences in efficacy.
• Patient needs to understand aims of treatment, and risks.
• Aim for as few drugs as possible, at as low a dose as possible.

Thiazides
• Eg. bendrofluazide.
• Inexpensive, effective.
• Increase HDL cholesterol and sugar.
• May precipitate gout.
• May cause impotence.

ACE-inhibitors
• Eg. captopril, enalapril, ramipril, lisinopril.
• Effective, but more expensive.
• Well tolerated.
• Contraindicated in presence of bilateral RAS (rapid worsening of renal function).

Calcium-channel antagonist
• Eg. nifedipine, verapamil, nicardipine, diltiazem.
• Effective, more expensive than thiazides.
• Lots of symptomatic toxicity:
-Constipation.
-Flushing.
-Ankle swelling.
-(Gum hypertrophy) - nifedipine.

β-blocker
• Eg. atenolol.
• Effective and inexpensive.
• Contraindicated in:
-Airways obstruction.
-PVD.
-Bradyarrhythmias eg. heart block.
-(Heart failure).
• Symptomatic adverse effects - tiredness, cold extremities.

Case
• BP remained high on 2 further outpatient visits.
• Cholesterol was unaffected by diet.
• Treated with enalapril and simvastatin September 1998.

Follow-up
• October 1998: still no lifestyle change. BP = 180/106.
• February 1999: cholesterol now 5.0. Enalapril dose now maximal. BP = 170/100.
• April 1999: BP = 160/96. Add thiazide.
• June 1999: BP = 140/92. Cholesterol 6.2. Simvastatin dose increased.

Emergency admission July 1999
• 2/24 of tight Retrosternal chest pain associated with:
-Sweating.
-Dyspnoea.
-Nausea.
• Pale, BO = 110/50. Fine basal crackles.

Tests and management
• ECG looking for ST segment changes.
• Trop-T.
• CXR.
• Diamorphine (with anti-emetic).
• FOLLOW PROTOCOL for streptokinase.
• Monitor.
• Aspirin.

Further follow-up
• September 1999: no change in lifestyle. BP = 160/94, cholesterol 5.5.
• November 1999: 2 episodes sudden loss vision in left eye. Carotid bruit noted.
• Diagnosis and investigations?

Tests
• Carotid Doppler studies: 80% occlusion of left carotid artery.
• Referred for vascular surgery opinion.
• Continued on aspirin.

Emergency admission 01.01.01
• Sudden onset right hemiparesis.
• Severe dysphasia.
• Unsafe swallowing.
• Deterioration to GCS 7/15.
• CT shows large haematoma on left.
• Cardiac arrest.

Hypertension CPC

2006-11-14T15:03:00.000Z

10.11.06

Case 1
• Male aged 42, software salesman.
• Non-smoker and light drinker.
• Colleagues said he was prone to unpredictable fits of rage, described as "like apoplexy."
• Apparently fit and well.
• Suddenly died while driving his car.

• Autopsy conducted at request of coroner.
• Enlarged heart 450g (LVH).
• No obvious thrombus/infarct.

Phaeochromocytoma
• Tumour of adrenal medulla.
• Produces NA.
• Paroxysmal release.
• 10% bilateral/malignant.
• Large, pleomorphic cells with vascular architecture. Dense core granules on electron micrograph.

Case 2
• Female aged 48 presents with asymptomatic systemic hypertension of 150/110, discovered at insurance medical.
• Company director.
• FH: father died age 49 of stroke, vague history of large kidneys.

Investigations
• U + E:
-Creatinine 410.
-Urea 16.
-Potassium 4.8.
• Hb 11.1.
• Creatinine clearance 35 ml/min.
• USS: bilateral large kidneys.
• IVU: poor excretion and large kidneys.

Polycystic kidney, another renal cause of hypertension
• Autosomal dominant.
• 1:500 births.
• 10% chronic renal failure needing treatment.
• Middle-aged onset of symptoms.
• Associated with cysts of other organs (liver 40%) and berry aneurysms.

Case 3
• Male aged 59, PE teacher, generally well, goes to gym and does weights.
• Presents with severe abdominal pain of sudden onset ("tearing").
• Shocked: BP 100/55 on admission.
• Not anaemic, U + E normal.

• Abdominal wall become discoloured, purplish-brown.
• Angiogram shows leaking aortic aneurysm.
• Stabilised, then…
• Taken to theatre urgently.
• Open repair of aneurysm.
• Makes full recovery.

Aortic aneurysm
• Predisposing factors:
-Hereditary.
-Atheroma.
-Syphilis.
• Sites.
• Treatment:
-Open.
-Endovascular.
• Normal diameter ~ 1.5-2.5cm.
• Risky >5cm.
• Likely to rupture in 12 months >6cm.
• Screening programme for people at risk (+FH).
• Endovascular repair somewhat better results than open (current BMJ data).

BP
• Measurement errors.
• 24-hour recording shows wide variation.
• Spikes possible in moments.

Case 4
• Female, aged 55, florist.
• Presents with severe headaches, not relieved by aspirin.
• Noticed swollen ankles lately.
• BP 190/140.
• U + E: sodium 148, potassium 5.1, creatinine 380, urea 16.8.
• Renal biopsy shows:
-Necrotising arteriolitis.
-Hyperplastic arteriolitis (onion-skinning).
-Necrotising glomerulonephritis.
• Fails to respond to aggressive antihypertensive therapy.
• Develops stroke - becomes comatose.
• CT brain shows subarachnoid haemorrhage.
• Some recovery occurs, but left with severe deficit.

Systemic Hypertension

2006-11-14T15:02:00.000Z

10.11.06

What is it?
• What is normal BP?
• Usually given in mmHg as 100 + age, but only in Western populations.
• What is abnormal level?
• Very variable definition - some debate about whether to treat ostensibly healthy population who are not symptomatic but may be at slight risk of complications.
• Diastolic >90 usually given as threshold level.
• Systolic >140 over period also - hypertension.

Prevalence/types
• Gives prevalence ~25%, increasing with age >50 years.
• More common in females (But less severe in older female group).
• 90-95% is essential type.
• Most of secondary type due to renal disorders (but others possible: endocrine, vascular, Neurogenic).
• Malignant (accelerated) hypertension: can occur in both essential and secondary types - ~5% hypertensive patients develop this.

Mechanisms
• BP = cardiac output x peripheral resistance.
• Concept of autoregulation - especially brain and kidney (but to some extent, all vessels).
• Cardiac output influenced by volume and cardiac activity factors.

Peripheral resistance influenced by:
• Neural (α, β adrenergic).
• Local (autoregulation, ionic, pH etc.)
• Dilators (prostagladins, kinins).
• Constrictors (angiotensin-II, catecholamine, thromboxane, leukotrienes).
• Also by atheroma affecting compliance of aorta.
• Coarctation.

Derangements
• Renin-angiotensin system: normally accurately controlled feedback mechanism.
• Increased renin important in:
-Unilateral renal artery stenosis.
-Malignant hypertension.
-Vasculitis.
-Pyelonephritis.
-JGA tumours, Wilms' tumour/carcinoma.
-Some cases of chronic renal failure of various causes.
• Sodium homeostasis: as well as angiotensin II, glomerular filtration rate and natriuretic factors have bearing on this.
• Sodium retention most important factor in hypertension of chronic renal failure, with which it is strongly associated.

Mechanisms of essential hypertension
1. Genetic (twins, blood relatives).
-Polygenic inheritance.
-?Role of imprinting.
2. Environment: dietary sodium most important?
-Variation of blood pressure with sodium intake locally.

Possible reasons
• Loss/defect of sodium excretion facility.
• Defect of sodium transport in cell membranes.
• Increased sympathetic response to stress/neurogenic factors.

Renal artery stenosis
• Accounts for 2-4% all hypertension, but treatable.
• Type works by JGA stimulation proportional to degree of stenosis.
• 70% cases due to atheromatous plaque at origin of artery.
• Fibromuscular dysplasia can also occur.

Other causes of secondary hypertension
• Renal.
-Acute glomerulonephritis.
-Renal polycystic disease.
-Renal involvement by vasculitis.
• Endocrine.
-Exogenous hormones.
-Steroid-producing tumours.
-Thyroid.
-Phaeochromocytoma.
• Neural.
-Acute stress.
-Sleep apnoea.
-Raised intracranial pressure.
-Psychological.
§Note: blood pressure can be lowered in some people by biofeedback methods.

Effects of hypertension: kidney
• Benign nephrosclerosis.
-Small granular kidneys with narrowed vessels and resultant ischaemic atrophy, glomerulosclerosis and tubular atrophy.
-Fibroelastic hyperplasia in larger arteries.
-Does not usually cause renal failure but will have reduced reserve.

Cerebral effects of benign hypertension
• Intracerebral haemorrhage + subarachnoid.
• Lacunae (minute infarcts in deep portions of brain e.g. basal ganglia and white matter).
• Subcortical leukoencephalopathy: diffuse loss of hemispheric white matter leading to dementia (probably ischaemic).

Hypertensive heart disease
• Left ventricular hypertrophy, usually of concentric type. LV >200g. May occur even at 140/90 i.e. 25% of population.
• Heart undergoes hypertrophy as result of increased workload.
• Eventually, leads to ischaemic fibrosis and decompensation.
• Can be diagnosed only in absence of other causes e.g. aortic stenosis.
• Coronary atherosclerosis interacts with (and is worsened by) hypertension.
• If blood pressure controlled, some evidence hypertrophy may regress. Especially true of ACE inhibitors.

Malignant hypertension - clinical features
• Diastolic >130, papilloedema, encephalopathy, renal failure and cardiac insufficiency.
• Often present with headaches/scotomas.
• May have hypertensive crises.
• Real emergency. Now 50% 5-year survival - much improved from previous rate.

Pathogenesis
• Very high levels of renin, angiotensin II and aldosterone.
• Interacts with endothelial damage to cause intravascular thrombosis, with more ischaemia and vicious circle.
• Sometimes coagulation may come first.
• Renal failure results from profound ischaemia.

Effects: kidney
• Malignant nephrosclerosis.
-Strongly correlated with previous benign hypertension/renal disease of another type.
-2 main changes.

Effects: brain
• Encephalopathy: associated with malignant hypertension, eclampsia and acute nephritis.
• Headache, drowsiness, stupor and coma.

The Cardiovascular System In Its Context

2006-11-14T15:01:00.000Z

6.11.06

Hypertension
• ABC of Hypertension: The Pathophysiology of hypertension, BMJ, 322: 912-916.
• Up to 5% patients with hypertension have it as secondary to some other disease e.g. renal disease.
• Rest have "essential hypertension."

Story so far…
Stroke volume

Cardiac output

Heart rate

• Intrinsic (Starling's law - "more in, more out").
• Extrinsic (principally autonomic.)

Postulated mechanism
• Increased sympathetic activity:
-Leads to increased cardiac output.
-And peripheral vasoconstriction (to protect capillary beds).
• Drop in blood flow triggers rennin-angiotensin system.

Evidence
• Cross transplantation studies show essential hypertension has origins in kidneys.
-Human and animal studies.
• Little evidence "stress" involved.
-But, of course, drugs that decrease sympathetic activity decrease blood pressure.

Control
BRAIN
Volume ANS
Pressure
Chemicals ADH

HEART BODY

Angiotensin

LOCAL BLOOD FLOW

Pressure
• Sensed by baroreceptors - in carotid arteries and aortic arch.
• Increase in pressure causes decrease in sympathetic activity.
• Decrease in pressure causes increase in sympathetic activity.

Volume
• Sensed by atrial volume receptors.
• Decrease in volume causes:
-Increase in ADH secretion.
-Decrease in ANP secretion.

Local blood flow (kidney)
Decreased renal blood flow

Monitored by JGA cells

Renin production

Angiotensin Angiotensin I

Converting enzyme

Angiotensin II

Sodium resorption
Aldosterone
Potassium secretion

Vasoconstriction

Hormones
• Angiotensin II = vasoconstrictor.
• Aldosterone increases vascular sensitivity to angiotensin II.
• ADH increases water resorption.
• ANP decreases sodium secretion.

Module 2.06

2006-11-14T14:59:00.000Z

Ignorance Is Bliss?
6.11.06 - 17.11.06.

Implementation Of A National Colorectal Cancer Screening Programme: The West Experience

2006-10-30T19:23:00.000Z

30.10.06

Wilson-Junger criteria for population screening
• Important health problem? YES.
• Early/latent stage? YES.
• Is natural history known? YES.
• Suitable screening test? YES.
• Agreed criteria for who should be treated? YES.
• Diagnostic and treatment facilities available? YES.
• Is programme economically viable? YES.

Is colorectal cancer important health problem? YES!

5-year survival [conditions completely curable]
• Stage 0: 100%.
• Stage I: 90%.
• Stage II: 65%.
• Stage III: 25%.
• Stage IV: 15%.

Proportion diagnosed so that can be cured [condition asymptomatic if confined to gut wall]
• Stage I: 11%.
• Stage II: 33%.
• Stage III: 33%.
• Stage IV: 23%.

If lucky, become anaemic: through investigation of anaemia, cancer becomes obvious.

Screening has two meanings
Opportunistic e.g. Europe, USA Population-based e.g. UK
Recruitment At patient-doctor consultation Systematic invitation of all eligible in population
Participation Low High
Objective Prevention of death in participants Reduction in population mortality
Total cost Low High

Performance of potential screening tests
Screening test Sensitivity Specificity
Faecal occult blood - guaiac 30-50% ~50%
Faecal occult blood - immune 54-89% >94%
Flexible sigmoidoscopy ~50% >95%
Colonoscopy ~95% >95%
CT colography 55-92% -
Faecal DNA test 41% 94%

Flexible sigmoidoscopy - MRC/CRUK "Flexisig" study
• One examination at age 55-60.
• Detects all distal adenomas.
• Detects 50% proximal adenomas.
• Recruiting closed 1999.
• Reports in 3-5 years' time.
• 4.7% normal 55-year-olds have high-risk lesions.
• In 40,000 55-year-olds, 140 cancers were found.
• ~ 55% patients with advanced proximal lesions do not have distal lesions.

CT virtual colonoscopy
>6mm >8mm >1cm
Sensitivity of virtual colonoscopy 86% 93% 92%
Sensitivity of optical colonoscopy 90% 90% 88%

DNA stool testing
• Panel of 21 mutations:
-3 x K-ras, 10 x APC, 8 x p53, Bat-26.
-Long DNA - indicative of apoptosis.
-APC and p53 most frequent mutations.
• Sensitivity for TNM I, II and III cancers 52% compared to 13% for haemoccult II.

What is screening protocol in England?
• Guaiac-based FOBT every 2 years.
• Age 60-69.
• Positive FOBT will have colonoscopy.
• Intermediate-/high-risk polyps: 3-year surveillance.
• Invitations for screening by letter.
• Patients identified by national database.
• Public education and advertising programmes.
• National quality assurance standards.

Detailed mathematical model of colorectal cancer screening constructed - each transition represented by range of probabilities.

Survival advantage: flex sig and FOBT decrease mortality - main advantage at age 70.

Preventing Colon Cancer

2006-10-30T19:22:00.000Z

30.10.06
Screening versus prevention.

Prolongation of life by colon cancer prevention in normal-risk individuals: statistical problem for organ-targeted screening
• 3% all deaths due to colorectal cancer.
• Median age >65.
• Life lost by death ~10 years.
• 15% reduction by acute blood screening prolongs life for average-risk individual by average of 10 days.
• Abolishing all deaths from colorectal cancer prolongs life on average by 3% of 10 years i.e. 4 months per person.

False positives present in screening - benefits of screening should be debated with individual.
Risk of death from colorectal cancer reduced by ~15% if screening carried out.

Colorectal cancer: questions to be answered
• Why do Westernised countries have more colorectal cancer?
• Why does the colon get cancer more often that the small intestine?
• What dietary factors are important?
• What are the mechanisms for interactions between diet and colon cancer?

Epidemiology of colon cancer
Correlated with increased risk: ↑ red meat
↑ calories
↑ body mass index
↓ exercise
↓ vegetables, cereals??
↓ calcium
↓ faecal pH
↓ selenium

Colon cancer and diet
• What dietary components are important?
• What are the mechanisms for their effects?
• What is important about the food?

Questions needing answers before reliable dietary advice can be given
• What foods should you eat? [E.g. which vegetables?]
• Where should they be grown? [Cf. selenium.]
• How should they be harvested? [Young sprouts.]
• How should they be cooked? [Burnt meat.]
• How quickly should they be eaten? [Is slowly, better?]
• Which foods are good for which genes? [Can slow acetylators eat roast beef?]
• Does it matter what food you eat if you take an aspirin a day?

Potential mechanisms for interactions between food and colon cancer risk
• Carcinogens.
↑ clearance of carcinogens.
• Pro-proliferative.
Anti-proliferative.
• Pro-apoptotic.
Anti-apoptotic.
• Anti-oxidant.
• ?Inhibition of interaction between bacteria and colonic epithelium.

Eating 1 pack peanuts per day for 1 week increases mitotic rate in rectal mucosa.

Risk for colon cancer determined at cellular level by:
(i) Mutation rate;
(ii) Mitosis rate;
(iii) Apoptosis.
Do we know which of these is most important? Increasingly, evidence pointing towards apoptosis.

Inflammation decreases arachidonic acid decreases apoptosis.

Two main types of genomic instability in colon cancer:
1. Chromosomal instability.
2. Microsatellite instability.

Conclusions so far:
BAD: High energy intake.
High intake red meat.
GOOD: Regular exercise.
Aspirin.
Non-legume green vegetables.
NEUTRAL: Cereal fibre.

Prevent 50% premature deaths from IHD, stroke and diabetes = 253 days saved.
Prevent 50% premature deaths from colorectal cancer = 42 days saved.

Conclusions
• Prevention in normal-risk population more likely to be taken up if also decreased risk for other common diseases.
• Colon-specific screening gives greatest benefit in high-risk groups: FAP and HNPSS relatives, high-risk family history, longstanding ulcerative colitis/Crohn's disease.

Module 2.05

2006-10-30T19:21:00.000Z

Rectal Bleeding.
23.10.06 - 3.11.06.

Abdominal Pain - 4

2006-10-17T17:55:00.000Z

Intestinal Obstruction
16.10.06

Causes of obstruction
SMALL INTESTINE
• Adhesions.
• Hernias.
• Neoplasms.
• Miscellaneous.

COLON
• Neoplasms.
• Volvulus.
• Diverticular stricture.
• Miscellaneous.

Intra-abdominal adhesions
• Common cause of small bowel obstruction: 66-75% cases.
• Exacerbated by intra-abdominal infection, ischaemia, foreign bodies.
• Any abdominal/pelvic surgery.
• 1 year post colectomy risk 11%, 10 years 30%.
• Variable interval between surgery and adhesive obstruction (7 months-65 years, average 6 years).

Hernias
• 2nd most common cause of small bowel obstruction (25%).
• Complete obstruction and strangulation related to rigid fascial defect through which hernia passes.

Neoplasms
• Unusual cause of small bowel obstruction (<10%).
• Usually extrinsic compression on local invasion by advanced GI (pancreatic, colonic, gastric)/gynaecological (ovarian) malignancies.

Pathophysiology
• Outcome depends on duration/degree of obstruction.
• Severity of ischaemia determines local and systemic pathophysiological consequences.
• Profound accumulation of fluid and swallowed air within intestinal lumen proximal to obstruction.
• Impaired water and electrolyte absorption and enhanced secretion → movement of isotonic fluid from intravascular space into intestinal lumen.
• Distension due to swallowed air, gases from bacteria and fluid.
• Failure of normal intestinal motility → bacterial overgrowth → translocation of bacteria to lymph nodes and systemic organs → systemic infection.

Presentation
• Acute onset of cramping mid-abdominal pain, vomiting, constipation, abdominal distension.
• Degree depends on degree of obstruction, site and duration.
• Paroxysms of pain every 4-5 minutes for proximal obstruction.
• Proximal obstruction: profuse vomiting, pain, minor abdominal distension.
• Distal obstruction: less frequent vomiting (but faeculent) and greater abdominal distension.

Examination
• Bowel sounds usually described as high-pitched/musical.

Abdominal x-ray
• If suspect obstruction, need AXR.
• Upright AXR: multiple air-fluid levels with loops of distended bowel resembling "U."

Contrast studies and CT
• Definite diagnosis, no obstruction, high-grade/complete obstruction in 50-80% patients studied.

Complete small intestine obstruction
• Complete - urgent laparotomy and broad-spectrum antibiotics.

Adenocarcinoma of colon
• >20% patients with colorectal cancer present with obstructive symptoms.
• Poor prognosis if need emergency surgery.

Volvulus
• Abnormal twisting of segment of bowel on itself along longitudinal axis.
• Results in occlusion of intestinal lumen, often closed loop obstruction → strangulation.

Diverticulitis
• Benign colonic strictures occur as consequence of diverticulitis, ischaemia and post-operative anastomotic strictures.

Pathophysiology
• Competency of ileocaecal valve important in Pathophysiology of colonic obstruction.
• If ileocaecal valve competent → caecum cannot decompress fluid and gas into small bowel → closed loop obstruction, fluid and gas accumulate → intraluminal pressure increased → colonic wall becomes ischaemic.

Presentation
• Periumbilical or hypochondriac pain and abdominal distension.

Benign and malignant colonic strictures
• Change in stool calibre/frequency.
• Malaena (or iron-deficiency anaemia).

Colonic volvulus
• Sigmoid volvulus usually 70-80 years.
• Caecal volvulus - younger sufferers.

Treatment and outcome
• Resuscitate as for small bowel obstruction.
• Obstructions proximal to Splenic flexure usually adenocarcinomas → right hemicolectomy and primary ileocolic anastomosis.
• If unfit → loop ileostomy.
• Obstruction distal to Splenic flexure either adenocarcinomas/Diverticular strictures.

Colonic pseudo obstructions
• Clinical picture suggestive of mechanical obstruction.
• Acute/chronic.
• Acute: symptoms as mechanical.
• Pathophysiology: imbalance in ANS (increased sympathetic and decreased parasympathetic tone).

Treatment
• Treat underlying cause.
• Correct electrolyte abnormalities.
• Drip and suck.
• Neostigmie.

Incidentally, this is the 100th post on this blog. Would you believe it?

Abdominal Pain - 3

2006-10-17T17:54:00.000Z

Upper Abdominal Pain
16.10.06

Peptic ulcer disease
• Defects in mucosa as result of acid-peptic juices.
• Causes:
-H. pylori (80%).
-NSAIDs.
-Pancreatic duct blockage.
-Zollinger-Ellison syndrome.
• Males 4X>females.
• Duodenal ulcers 2-3X>gastric ulcers.

Causes
• Early 20th Century - stress and diet.
• 1950s - acid.
• 1970s - H2 receptor antagonists - ulcers chronic incurable.
• 1980s - PPIs; H. pylori.

Symptoms
DUODENAL ULCER
• Burning/gnawing in epigastrium.
• Occurs 2-3 hours after meal.
• Relieved by ingestion of food/antacids.
• 2/3 pain wakes in middle of night.
• Anorexia and weight loss unusual - can put on weight.

GASTRIC ULCER
• Burning/gnawing in epigastrium.
• Sooner after meals than duodenal ulcer.
• Not relieved/worsened by food and antacids.
• 1/3 wake from sleep with pain.

Complications
• Haemorrhage.
• Perforation, leading to peritonitis.
• Scar tissue build-up, leading to obstruction.

All gastric ulcers must be biopsied to exclude gastric cancer.
Duodenal ulcers are never malignant.

Treatment
• If H. pylori positive: H. pylori eradication triple therapy - PPI + 2 antibiotics.
• If H. pylori negative: PPI.
• Perforation needs urgent surgery.
• Haemorrhage: endoscopic therapy.

Acute cholecystitis
• Usually caused by gallstones.
• Gallstone affect 10% in West.
• 80% asymptomatic.
• Helminthic infection (ascariasis) major cause of biliary disease in developing countries.
• Obstruction of cystic duct → inflammation → acute cholecystitis.

Risk factors for gallstones
• Age >40 years.
• Bile salt loss (ileal disease/resection).
• Female sex (twice risk than men).
• DM.
• Genetic/ethnic variation.
• CF.
• High fat, low fibre diet.
• Obesity.
• Gall bladder dysmotility.
• Pregnancy.
• Etc.

Pathophysiology of cholecystitis
• 90% acute cholecystitis caused by obstruction of cystic duct by gallstones/sludge.
• Increase in intraluminal pressure and cholesterol supersaturates bile.

Clinical presentation
• Sudden onset pain in epigastrium.
• Can radiate round to back in intrascapular region.
• Pain often does not fluctuate, but persists 15 minutes - 24 hours.
• Nausea or vomiting common.
• Peritonitis localised to RUQ.

Investigations
• USS investigation of choice.
• Pericholecystic fluid.
• Distended gall bladder.

Management
• Fasting, IV fluids and analgesia.
• 20% need emergency surgery.
• Cholecystectomy.

Complications
• Gangrenous cholecystitis.
• Gall bladder perforation.
• Cholecystoenteric fistulas.

Jaundice and gall stones
• Most commonly occurs when stone migrates from gall bladder into common bile duct.
• LFT cholestatin pattern.

Acute pancreatitis
• >80% with alcohol/gallstones.
• Proteolytic enzymes activated → local and systemic inflammatory cell response.
• Often self-limiting.
• 5-20% fulminating course - pancreatic necrosis and cytokine activation → multiple organ dysfunction syndrome.

Symptoms
• Presentation variable.
• Alcohol-induced - symptoms 6-12 hours after binge drinking.
• Pain in epigastrium radiates to back.
• Associated with nausea and vomiting.
• Severe attacks mimic perforation/ischaemic bowel and "ruptured" aortic aneurysm.
• Abdominal distension.

Diagnosis
• Appropriate clinical features.
• Serum amylase activity over 3X normal.

Clinical course
• Self-limiting in 80% cases.
• Severe cases have 3 phases.

Assessing severity - initial predictors
• 1st attack alcohol induced.
• Obesity.
• Haemodynamic instability.
• Severe signs.

Severe pancreatitis
• Adequate resuscitation of hypovalaemic shock.
• Monitor urine output.
• Antibiotics - minor benefit.
• May need ventilation/dialysis.

Prognosis
• Overall mortality 10-15%.
• Not changed in past 20 years.

Abdominal aortic aneurysm
• True arterial aneurysms >50% increase in normal diameter of vessel.
• 90% mortality from ruptured abdominal aortic aneurysm, 80% die before reaching hospital and 50% die during surgery.
• Complications: rupture, thrombosis.

Presentation
• ¾ asymptomatic.
• Symptoms usually result from embolisation/rupture of aneurysm.
• Triad of hypovolaemic shock, pulsatile abdominal mass and abdominal/back pain in minority.

Factors predisposing to ruptured abdominal aortic aneurysm
• Diameter of aneurysm.
• Diastolic BP.
• COPD.
• Smoking.
• FH of ruptured aneurysm.
• Expansion rate.
• Etc.

Diagnosis
• Can usually palpate pulsatile mass.
• CT best test.

Treatment
• All should be considered for emergency surgical repair.
• Patients with symptomatic aneurysms need urgent aneurysm repair.

Non-abdominal causes of abdominal pain
• MI.
• Pneumonia, PE.
• New-onset DM.
• Addison's disease.
• Porphyria.
• Lead poisoning.

Conclusions
• Symptoms and signs often lead to correct diagnosis of acute upper abdominal pain.
• Remember non-abdominal causes of upper and mid-abdominal pain.
• USS early if atypical pain and aortic aneurysm suspected.

Abdominal Pain - 2

2006-10-14T19:26:00.000Z

Lower Abdominal Pain
13.10.06

Irritable bowel syndrome
Epidemiology
• IBS affects 9-20% of population.
• Very dependent on criteria.
• In 1year, 38% will resolve and 8% develop new IBS.
• Female: male ratio = 1.1 to 2.6.
• Age and race have no consistent effect on incidence of symptoms.

Presentation
• Only small fraction seen by gastroenterologists.
• 50% do not seek medical advice.
• Large spectrum of severity.
• Often referred to other specialties.

Abdominal symptoms
• Almost universal symptoms.
• Colicky abdominal pain.
• Bloating.
• Sensation of increased flatus production.
• Rectal dissatisfaction.
• Often upper GI symptoms of heartburn, early satiety.

Associated symptoms
• Increased urinary frequency.
• Urinary dissatisfaction.
• Headaches.
• Atypical chest pain.
• Fibromyalgia.
• Chronic fatigue.
• Menorrhagia, dyspareunia.

Rome II criteria
At least 12 weeks in last 12 months of abdominal discomfort/pain that has 2 out 3 of following features:
• Relieved by defaecation.
• Onset associated with change in frequency of stool.
• Onset associated with change in form of stool.
Supportive symptoms
• <3 bowel movements per week.
• >3 bowel movements per day.
• Straining during bowel movement.
• Hard/lumpy stools.
• Urgency.
• Etc.

Approach to diagnosis
• Positive diagnosis and minimise investigation.
• Typical symptoms without alarm symptoms - weight loss, nocturnal symptoms.
• Normal UEC, LFT, FBC, CRP, TFT.
• Screen for coeliac disease.
• Search for depression.

Pathogenesis
• Abnormal bowel motility.
• Visceral hypersensitivity.
• Psychological factors.
• Post-infective.
• Post-surgical.
• Abnormal colonic fermentation and gas production.
• Food intolerances.

Treatment
• Careful explanation - benign nature.
• Normal diet.
• ?Increase fibre.
• Antispasmodics helpful - mebeverine, alverine.
• Tricyclic antidepressants.
• Relaxation therapy.
• Hypnotherapy.

Problems with trials in IBS
• High placebo response.
• High drop out rate.
• Safety issues.

Appendicitis
• Appendectomy most common abdominal operation.
• Diagnosis difficult at extremes of life.
• 20% normal and up to 40% misdiagnosis especially in women.
• No such thing as grumbling appendix.

Signs
• Fever.
• Guarding.
• Rebound tenderness.
• Indirect tenderness.
• Psoas sign.

Symptoms
• RLQ pain.
• Nausea.
• Vomiting.
• Onset of pain before vomiting.
• Anorexia.

3 most predictive signs
• Pain in RIF.
• Abdomen rigidity.
• Migration of pain from periumbilical region to RIF.
Other factors
• Short duration of pain than with other disorders.
• Atypically presents with back pain, LIF pain.

RIF pain in women
• Most common misdiagnoses in women with:
Pelvic inflammatory disease.
-Gastroenteritis.
-UTI.
-Ruptured ovarian follicle, ectopic pregnancy.

PID more likely if:
• History of PID.
• Vaginal discharge.
• Urinary symptoms.
• Tenderness outside RIF.

Laboratory tests
• b-HCG level.
• 70-90% increased WCC, but not specific.
• MSSU.
• 40% of acute appendicitis have pyuria, haemuturia or bacteriuria.
• CT more accurate and better at identifying other diagnoses and complications that ultrasound scan.

Crohn's disease
• Idiopathic inflammatory bowel disease.
• Occurs anywhere from mouth to rectum.

Signs/symptoms
• Young Caucasian.
• Diarrhoea (80%).
• Abdominal pain (70%) - usually colicky lower abdomen.
• Occasionally obstructive symptoms.
• Weight loss (50%).
• Extra-GI symptoms.
• Examination - usually normal.
• RIF mass/fullness.

Smoking
• Probably most important intervention: stopping smoking.
• Smokers with CD have:
-More relapses.
-More pain.
-More operations.

Extra-GI manifestation
• Arthralgia.
• Mouth ulcers.
• Iritis.
• Etc.

Diagnosis
• Clinical.
• Raised inflammatory markers.
• Endoscopy.

PID
• Usually caused by invasion of either gonorrhoea/chlamydia from cervix up to uterus and tubes.
• Bacteria and neutrophils fill tubes.

Risk factors
• Low socioeconomic status.
• Multiple/high-risk sexual partners.
• Intrauterine contraceptive device.
• Previous episode.

Symptoms/signs
• Lower abdominal/pelvic pain.
• Dyspareunia.
• Dysuria.
• Abnormal uterine bleeding.
• Nausea and vomiting.
• Fever.
• Etc.

Investigation
• Increased WCC, ESR and CRP - non-specific.
• USS and CT.
• Laparoscopy.

Management
• Oral/IV antibiotic regimes.
• Ofloxacin.
• Ceftriaxone and doxycycline.

Ectopic pregnancy
• Most common location: Fallopian tubes.
• Pregnancy outgrows tube, tube wall ruptures.
• Haemorrhage into pelvic cavity occurs.

• Suspect in females of child-bearing age with:
-Abdominal pain.
-Unexplained shock.
• When was LNMP?
-Does not necessarily cause missed period.

Conclusions
• Pattern of pain and associated symptoms vital in making diagnosis.
• Functional pain most likely cause in younger adults.
• Important to think of PID, but difficult to diagnose.
• RIF pain in females most difficult.

CPC: Causes Of Abdominal Pain

2006-10-14T19:25:00.000Z

13.10.06

Acute abdomen: principles
• Intestinal obstruction - causes:
-Ileus.
§Vascular event.
-Obstruction.
§Intussusception.
§Volvulus.
§Hernial entrapment/incarceration.
§Due to tumours.

Complication of acute abdomen
• Peritonitis.
• Septicaemia.
• Shock:
-Definition.
-Types.
-Systemic inflammatory response syndrome.
Appendix
• Acute appendicitis.
• Threadworms.
• Carcinoma.
• Faecoliths.

Diverticular disease
• Pressure in large bowel.
• Effect of diet.
• Commonest in sigmoid colon.
• Weak points in wall.
• Diverticulosis and diverticulitis.

Chronic idiopathic inflammatory bowel disease
• Crohn's disease.
• Ulcerative colitis.
• Differences:
-Age/sex of index patients.
-Distribution.
-Wall involvement.
-Activity, granulomas.
-Complications.

Ovarian cancer
• 7000 new cases every year.
• Often presents insidiously i.e. later.
• Therefore, poor prognosis.
• Treatment difficult.
-Surgical clearance often not possible.
-Chemotherapy ~50%/year survival.
• Screening programme under discussion.

Neoplasia - 1

2006-10-14T19:24:00.000Z

13.10.06

Terminology
• Cancer: all malignant disease.
• Neoplasm: any autonomous growth.
-Benign or malignant.
• Malignant: shows invasion and/or metastasis.
• Benign: local growing only.
• Tumour: a swelling.
-[But colloquially = cancer.]
• Non-neoplastic "tumours."
-Choristoma, hamartoma.
• Dysplasia: cellular and architectural changes of neoplasia.
• Anaplasia: lack of differentiation, marked pleomorphism.
• Differentiation: degree to which neoplastic tissue resembles normal equivalent.
• Carcinoma: epithelial malignancy.
• Adenocarcinoma: malignancy of glandular tissue.
• Sarcoma: mesenchymal/connective tissue malignancy.
• Lymphoma: solid malignancy of immune system.
• Leukaemia: malignant blood cells in blood.

Definition of neoplasm:
• Abnormal mass of tissue, growth of which exceeds and is uncoordinated with that of normal tissues and persists in same excessive manner after cessation of stimulus that evoked change.

Cancer - the size of the problem
• 1 in 3 people will get it.
• 1 in 4 will die from it.
• England and Wales deaths from cancer: ~150,000/year.
• Mainly in older age groups but important, rarer types in children and young people.
• "Genetic" types occur at younger ages.

Theory of neoplasia
• Stem cell defect, often with chromosomal abnormality, resulting in expression of oncogenes or deletion of anti-oncogenes.
• Clonal theory, clonigenic cells.
• Versus field change.

Histogenic classification
• Clonal theory results in:
• Histogenic classification:
-Differentiation may vary in subclones.
-Other components: stroma, blood vessels, inflammatory cells.

Expansion
• Doubling times.
• Cell loss from tumour.
• Submutation and clonal evolution.
• Tumour angiogenesis.
• Mechanisms of invasion and metastasis.
-Detachment, invasion, spread to planes and vessels, embolisation, implantation.

E.g. colorectal tumour

Normal

APC loss/mutation

Metaplasic polyp

Loss of DNA methylation

Adenoma

Ras mutation (12p)

Adenoma

Loss of DCC (18q)

Late adenoma

Loss of p53

Carcinoma

Epithelial neoplasms
• Spectrum of benign, dysplasia, carcinoma in situ, invasive carcinoma.
• Concept of intra-epithelial neoplasia.
• Cytogenic and flow of cytometric abnormalities.

Features of dysplasia
• Loss of polarity (maturation towards surface).
• Basal cells above bottom layer.
• Mitoses above basal layer.
• Heaping up of layers.
• Individual cells show features of atypia.

Carcinogenesis
• Initiation and promotion.
• Multistep transformation.
• Mutations:
-Balanced translocations.
-Deletions.
-Gene amplification.
-Amplification.
-Extra/deleted chromosomes.

Mechanisms
• Initiation.
-Permanent change to DNA, mutations.
-Requires replication to stabilise it.
• Promotion.
-Reversible change, not capble alone of producing tumour.
-Allows changes of initiation to become effective.
• Mainly apply to chemical carcinogenesis.

Principal agents
• Radiation:
-Ionising.
-Non-ionising.
• Chemicals.
• Micro-organisms:
-Viruses.
-Bacteria.

Radiation carcinogenesis
• UV:
-A: 320-400nm.
-B: 280-320nm.
-C: 200-280nm.
• Damage pyrimidine dimers.
• Ras and p53 mutations.
• Cell mediated immunity reduced.
• Ionising:
-X-rays, γ-rays.
-Particles.
• Sources:
-Radiology.
-Radiotherapy.
-Miners.
-Bomb survivors.
-Chernobyl.
-Radiation workers.

Viral carcinogenesis
• Animal viruses (historical/experimental).
• HUMAN VIRUSES.
• HPV (especially 16, 18, 33 35, 51).
• EBV (Burkitt's, NPC, AIDS-lyphoma).
• Hepatitis B (and C).
• HTLV-1 (T-ALL and NHL).

Bacterial carcinogenesis
• H. pylori.
-Gastritis.
-Gastric ulcers etc.

Chemical carcinogenesis
• Initiators.
• Direct acting (electrophilic).
-Alkylating and acylating agents.
• Indirect (cytochrome p450 dependent).
-Polycyclic hydrocarbons.
-Aromatic amines.
-Plant and bacterial/fungal.
-Man-made.

Abdominal Pain - 1 or MORRISSEY HAS BINGO WINGS

2006-10-09T14:46:00.000Z

Structure And Function/Approach To Diagnosis
9.10.06

Abdominal pain
• Common, often trivial.
• But can be acute and severe pain.
• Gangrene/perforation of gut occur rapidly after interruption of blood supply.

3 types of abdominal pain:
• Visceral pain.
• Parietal pain.
• Referred pain.

Nerve fibres
• 2 types:
-Myelinated A-δ fibres (skin and muscle).
-Unmyelinated C fibres (mesentery, peritoneum and viscera).
• Nociception from abdominal viscera conveyed by C fibres - dull pain.

Visceral pain
• Noxious stimuli trigger visceral nociceptors.
• Pain dull and poorly localised in midline epigastrium, periumbilical region or lower midabdomen.
• Pain cramping/burning/gnawing.

Position of pain and anatomy
• Foregut:
-Stomach.
-Duodenum.
-Hepatobiliary system.
-Pancreas.
• Midgut:
-Small bowel.
-Ascending colon.
-Appendix.
• Hindgut:
-Hepatic flexure → rectum.
-Reproductive organs.

Parietal pain
• Noxious stimulation of parietal peritoneum.
• More intense and localised e.g. course of appendicitis.
• Aggravated by movement/coughing.
• Patient lies still with knees up.

Referred pain
• Pain felt in areas remote to diseased organ.
• Convergence of visceral afferent neurones with somatic afferent neurones from different anatomic region on second-order neurones in spinal cord at same spinal segment.
• Usually well-localised.

History
• 70% diagnoses can be made based on history.
• 90% diagnoses can be made based on history and physical examination.
• Expensive tests often confirm what is found during history and examination.

Age important in diagnosis.

Key points
• Chronology (time course).
• Location/quality.
• Radiation.
• Associated symptoms.

Location of abdominal pain clue to cause.
Can get combination of visceral, somatoparietal and referred pain.

Pain intensity
• Difficult to measure.
• Depends on individual, setting, past experience, personality and cultural differences.
• Not particularly reliable diagnostic clues.

Aggravating/alleviating factors e.g.
• Peritonitis - lie motionless.
• Renal colic - writhe to try and get comfortable.
• Duodenal ulcer - often helped by meals.
• Gastric ulcer/chronic mesenteric ischaemia - worse with eating.

Associated symptoms and review of systems
• Fever/night sweats.
• Weight loss, myalgias, arthralgias.
• Anorexia, nausea, vomiting, diarrhoea, constipation.
• Jaundice.
• Urinary frequency, urgency, discomfort.
• Sexual activity, contraception, LNMP and pregnancy.

PMH and SH
• ?Previous episodes e.g. renal stones, inflammatory bowel disease.
• Generalised diseases e.g. scleroderma, lupus, nephritic syndrome.
• Family history.
• Social history.

Examination - general points
• History much more important.
• Elderly less likely to show signs of peritoneal irritation.
• Systemic examination as important as abdominal examination.

Systemic examination
• Appearance.
• Breathing pattern.
• Position in bed and posture.
• Degree of discomfort.
• Pulse - tachycardia important sign.
• Blood pressure.
• Chest examination.
• Cardiovascular examination.
• Features of shock.
• Features of underlying systemic disease.

Inspection
• Distension.
• Scars.
• Hernias.
• Bruises.
• Visible hyperperistalsis.

Palpation
• Degree of tenderness, guarding, rigidity.
• Palpable mass.
• Hernia orifices should be examined.

Auscultation
• Bowel sounds:
-Absent = possible peritonitis.
-Tinkly sounds = possible bowel obstruction.

Investigations - laboratory
• U+Es.
• Hb, WCC.
• LFTs.
• Amylase.
• Urinalysis.
• Pregnancy test.

Radiology
• Chest X-ray and plain abdomen X-ray.
• Ultrasound.
• CT.
• MRI.

Learning points
• 3 main types of abdominal pain.
• Knowledge of basic neuroanatomy.
• Patterns of common causes of abdominal pain.
• Important points in history of abdominal pain.

Module 2.04

2006-10-09T14:45:00.000Z

The Civil Servant's Examinations.
9.10.06 - 20.10.06.

Drugs For GI Problems

2006-10-09T14:44:00.000Z

6.10.06

Nausea and vomiting
Antiemetics
• Anticholinergics* e.g. hyoscine - side effects: dry eyes, dry mouth, can affect urinary retention in old men.
• Antihistamines* e.g. promethazine - causes drowsiness.
• Phenothiazines+ e.g. prochloperazine - work on chemoreceptor trigger zone and vomiting centre - very effective.
• Dopamine receptor antagonists+ e.g. metoclopramide - work on chemoreceptor trigger zone and vagal afferent.
• 5-HT3 antagonists e.g. ondansetron - used for cancer-induced nausea.
• Others e.g. dexamethasone.

*Work on vomiting centre.
+Drugs of choice.

Dyspepsia
Symptoms
• Epigastric discomfort.
• Anorexia.
• Retrosternal pain.
• Nausea.
• Vomiting.
• Fullness.
• Early satiety.
• Heartburn.

Aetiology
• GORD - 15-25%.
• Ulcers - 15-25%.
• Stomach cancer - 2%.
• NUD - 60%.

Causes
• Acid reflux.
• Abnormalities of gastric acid secretion e.g. gastrin-secreting tumour i.e. Zollinger-Ellison syndrome.
• H. pylori - produces inflammation - hypersecretion of HCl.
• Stress - vagus nerve stimulates over-production of gastrin and histamine.
• NSAIDS, steroids, alcohol and other drugs.

Age-related management
Dyspepsia

<45>45 years

Nil alarming Alarm signs

Endoscopy

Alarm signs
Anorexia.
Loss of weight.
Anaemia.
Rapid progression.
Malaena.
Dysphagia/odynophagia.

Treatment
• Bismuth - coats mucosa - rarely used any more.
• Antacids - neutralise acid - remove symptoms at low doses - curative at high doses.
• PPIs - at apex of cell - more potent than H2A.
• H2 antagonists - at base of cell.
• Antibiotics - eradicate H. pylori.
• Anticholinergics.

Antacids
• Weak alkali.
• Relieve symptoms.
• Increase gastric emptying.

GORD
• Incompetent gastro-oesophageal sphincter.
• Hiatus hernia.
• May results in strictures.

Treatment
• Antacids and alginate.
• High-dose PPI - anti-secretory.

Diarrhoea
• Common complaint.
• Often settles spontaneously.
• Treat CAUSE rather than symptom.

To treat symptom:
• Stimulate opioids receptors - disrupt peristalsis - more time to digest.
-Loperamide/diphenoxylate/codeine phosphate.
• Absorbents:
-Kaolin.
• Anti-spasmodics (antincholinergics):
-Mebeverine/propantheline.

Constipation
• Bulking agents.
• Osmotic agents.
• Stimulants.
• Faecal softeners.

Inflammatory bowel disease
• Ulcerative colitis/Crohn's disease.

Anti-inflammatory drugs
• Steroids (oral, enema).
• Azathioprine.
• Sulphalazine (=sulphapyridine + 5-ASA).
• 5-ASA:
-Mesalazine (sustained release).
-Osalazine (2 x 5-ASA).

Acute Pancreatitis

2006-10-09T14:43:00.000Z

2.10.06

Definition:
• Acute inflammatory process of pancreas, with variable involvement of other regional tissues or remote organ systems.

Why is it important?
• Common abdominal disease:
-Always a differential in abdominal pain.
-Common admission on acute surgical take.
• Spectrum of clinical presentations:
-Mild, self-limiting disease.
-Apocalyptic destruction of pancreas, multi-organ failure and death.
• Therapy essentially limited to supportive care.

Pancreas - a little history
• "Discovered" by Herophilos (335-280 BC).
-Alexandrian physician and anatomist.
-"Father of anatomy."
• Named by Ruphos.
• Galen:
-Claimed pancreas was cushion - to protect vessels behind.
-Word was "law" - not questioned for ~1500 years.
• Wirsung:
-Discovered pancreatic duct named after him.
• Langerhans.
• Banting and Best:
-Discovered insulin (in dog).
-6 months later, 14-year-old boy with diabetes treated with insulin.
-18 months later, mass-marketed.
-Nobel prize in 1923 (Best omitted).
• Digestive enzymes.
-Discovered throughout mid-late 19th Century.
• Wohlgemuth:
-Discovered amylase.
-Introduction to potential to diagnose pancreatitis.

Embryology
• Ventral bud - close to bile duct.
• Dorsal bud - in dorsal mesentery.
• Both have own duct.
• Duodenum rotates to right.
• Ventral and dorsal portions fuse.
• Ventral portion form uncinate process and inferior head.
• Dorsal portion forms rest of head, neck and tail.
• Ventral and dorsal ducts fuse to form main pancreatic duct (Wirsung's).

Anatomy
• Retroperitoneal.
• Immediately posterior to stomach.
• Space between stomach and pancreas form anterior and posterior borders of lesser sac.

Physiology
• Endocrine:
-Mainly body and tail.
-Islets of Langerhans.
-Insulin - β cells.
-Glucagon - α cells.
-Somatostatin - δ cells.
• Diabetes mellitus.
• Exocrine secretion:
-1500ml per day.
-Digestive proenzymes (zymogens):
§Carbohydrates (amylase).
§Proteins (pro-trypsin, pro-chymotrypsin, pro-carboxypeptidase, pro-elastase).
§Fats (pro-lipase, pro-phospholipase).
-HCO3- - alkalinises duodenal contents.
-Stimulated by CCK, secretin, vagal tone (ACh).

Pathogenesis
Idiopathic.
Gallstones.
Ethanol.
Trauma.
Steroids.
Mumps (and other viruses).
Autoimmune disease.
Scorpion sting (tityus trinitatis).
Hyper- Ca2+/lipids (and hypothermia).
ERCP.
Drugs (SAND - steroids/sulphonamides, azathioprine, NSAIDS, and something beginning with 'D' that I didn't get because he was started to panic about the time.)

• Gallstones:
-Impacting at ampulla.
-Flow of bile up pancreatic duct.
-?Increased pressure up duct.
• Most passed by time of admission.
• Other complications of obstructed bile duct.
• ERCP.
• Scorpion:
-South American scorpion.
-Venom causes haemorrhagic pancreatitis.

• Most common in Western world.
• Rising alcohol consumption in young.
• Leads to chronic pancreatitis.

• Premature enzyme activation within acinar cell.
• Normally trypsin activated in duodenum by enterokinase.
• Mechanisms in acute pancreatitis unknown.
-Disordered Ca2+ signalling shown to be crucial.
-Bile salts and alcohol metabolites shown to lead to enzyme activation in experimental pancreatitis.
• Exact site controversial - many theories e.g.
-Activation within zymogen granules.
-Disordered manufacture, storage or packing of zymogen etc.

Events in acinar cell
• Premature enzyme activation.
• Disruption of cell structure.
• Loss of apical enzyme secretion.
• Formation of apical vacuoles.
• Lysosomes fuse with granules.
• Inflammatory signals released.
• Cell death ensues at later stage.

Local
• Destruction of pancreas:
-Malabsorption.
-Diabetes mellitus.

Regional
• Pseudocyst (after 4 weeks):
-Obstruction.
-Haemorrhage.
• Splenic artery thrombosis.

Systemic
• Cytokines response.
• Multi-organ failure.
• Cardio-respiratory/coagulopathy/renal failure etc.

Incidence
• 3% of all cases of abdominal pain admitted in UK.
• Incidence ~15-420 cases per million per year.
• Overall mortality has dropped:
-From 30% to 6-10%.
-No further drop over decade.
-80% have mild, self-limiting attack/20% have severe disease.
-Up to 40% mortality in severe group.

Presentation
• Symptoms:
-Severe abdominal pain.
-Radiation through to back.
-Nausea +/- vomiting.
• Signs:
-Biliary pancreatitis.
-Alcoholic pancreatitis.
-Ecchymosis to abdominal wall.
§Cullen's sign.

Clinical assessment
• Majority: increased temperature, increased respiratory rate, increased pulse, decreased blood pressure.
• Shock - inadequate tissue perfusion leading to cellular hypoxia.
• SIRS:
-Temperature >380C (or <360C).
-Heart rate >90 bpm.
-Respiratory rate >20 per minute.
-White cell count >12 x 103.
• Sepsis.

Bloods
• Diagnostic.
• Amylase (4X upper limit of normal) - rises 2-12 hours/normalises <7 days, ~10% normal in acute-onset pancreatitis.
• Lipase (2X upper limit of normal) - rises 4-8 hours/normalises 8-14 days - more acute than amylase, but less available.
• FBC.
• U + Es/LFTs/serum Ca2+.
• Arterial blood gas:
-Pa O2, acidosis.

Investigations
• Plain radiographs.
-Erect chest and plain supine abdomen.
-Exclude other pathology.
-Baseline films (especially with later events).
• USS.
-Detects free fluid, gallstones, dilatation of CBD.
• CT.
-Not in first 48 hours.
-Intrapancreatic.
-Shows necrosis/acute fluid collections/abscesses.

Scoring
• Ransom criteria.
• Glasgow score modified from Ransom criteria for all patients.
• APACHE-II.
• APACHE-0.

Management
• General measures.
• Specific measures:
-ITU.
-Antibiotic therapy.
-Nutrition:
§"Drip and suck" - old thinking.
§Early nutrition.
§Use enteral route if possible (oral/NG/NJ feeding).
§"More physiological" - protective "gut barrier."

Interventions
• ERCP.
• Surgery:
-Infected necrosis.
-Pseudocyst:
§Collection of inflammatory fluid > weeks.
§Enzymes, blood, necrotic tissue.
§Symptomatic - obstruction/infection.
§Endoscopic.

Surgery
• Open versus closed.
• Open necrosectomy:
-Conventional procedure.
-Laparotomy.
-Pancreatic necrosectomy.
• Closed necrosectomy.

A Burning Question: Inflammation - Acute And Chronic

2006-10-01T15:11:00.000Z

29.9.06

Inflammation
• Results from injury.
• Organised set of defence responses.

Cellular injury - causes
• Physical.
• Radiation.
• Chemical.
• Ischaemic.
• Free radicals.
• Infection - has elements of several of these.

Inflammation
• Acute - stimulus involved.
• Chronic - stimulus persists.

Acute inflammation
• Cardinal signs:
-swelling (tumor);
-heat (callor);
-redness (rubor);
-pain (dolor);
-loss of use.
• Vascular change:
-permeability;
-pressure.

Inflammatory mediators (chemotactic, chemokinetic)
• Plasma protein cascades:
-complement;
-kinins;
-blood clotting;
-fibrinolytic.
• Intracellular, sorted, released on demand:
-histamine (vasoactive) from mast cells;
-serotonin: platelets and enterochromaffin cells (not mast cells);
-lysosomal enzymes (proteases).
• Synthesised and released from cells:
-prostaglandins (peroxidation of arachidonic acid) - pain and fever in inflammation;
-leukotrienes (lipo-oxygenase pathway) - activate Neutrophils (adhesion, free-radicals, enzymes);
-platelet activating factor;
-cytokines:
§interleukins (IL1-IL15) - IL1 and IL6: systemic acute phase responses;
§interferons (α, β, γ);
§cytotoxins (TNF-α and lymphotoxin).

Complement
• Opsonisation.
• Membrane attack complex (cell lysis).
• Proteolysis.
• Mediators for vascular and cellular pathways (anaphylatoxins C3a and C5a - cause histamine release).
• Classical pathway: antibody-mediated.
• Alternative pathway: LPS-mediated.

Kinins
• Hageman factor (factor XII) activates:
-factor XI to initiate clotting;
-plasminogen proactivator (fibrinolytic);
-prekallikein cleaved → kallikrein;
-kininogen → bradykinin;
-short-lived, but:
§increased vascular permeability;
§and something else, but nobody got it because he moved onto the next slide far too quickly.

Phagocytosis
• Neutrophils adapted for bacterial ingestion.
• Opsonisation by complement/specific immunoglobulin.
• Oxidation of organism by superoxide anion, H2O2, OH• radical and HOCl. Presence of myeloperoxidase required.
• Macrophages attack larger particles (but also some bacteria).

Defence against invasion
• Complement system.
• Non-specific defences.
• Immune system.
• Phagocytosis - opsonisation.

Chronic inflammation
• The immune system - lymphocytes, plasma cells.

Prescribing In The Community

2006-10-01T15:10:00.000Z

25.9.06

Thanks to Marion for these.

Elderly are biggest consumer of drugs on prescription
• Less therapeutic variation (dose standard).
• Better evidence of effect - more obvious.
• Increasing elderly population.
• Defensive behaviour by doctor - in case they miss something.

Don't pay for prescriptions over 60/65?

40% take inappropriate drugs.
50% of hospital admissions due to adverse drug events are due to inappropriate prescribing.
Huge increase in prescribed drugs in over-65s since 1977.

Who prescribes?
• Doctors, mostly.
• Dentists - mostly antibiotics.
• Nurses - new act - antibiotics and fluids.
• Pharmacist.
• Patients/carers eg. paracetemol etc. - self-medication.

Process is flawed
• Prescriptions often written based purely on clinical acumen - presumptive diagnosis.
• Patient/carer often takes it to chemist - can be lost.
• Processed by hand - writing often hard to read.
• Renewal of prescription often without adequate counselling.
• Generation:
-not much else to think about;
-health is most crucial thing to them - drugs are exciting point of day.

Prescribing
• How to chose? Cost/industry reps/scientific evidence/efficacy/SE.
• Increasing availability of drugs - increasing complexity.
• Demand from patients - now well-informed.
• Increased volume of prescriptions - increasing risk of errors, less time for patient counselling.

Challenges
• Increased prescriptions and OTC meds - more mortality and morbidity associated.
• High financial costs due to morbidity (drug-related).
• Poorly-written prescription - pharmacists have to call prescriber, leading to another cost.

Patient safety
• Medication errors and adverse drug effects - result of interactions between prescribers, patients and medications.
• Need full picture of what's going on.
• High costs - financial and human - due to ADEs.
• Lack of access to patient information contributes to ADEs eg. in hospital and on discharge.
• Move to standardise NHS practices so information can be shared.

Barriers
• Lack of integration - this is changing slowly.
• Politics based on industry competition.
• Dave likes boys.
• Can the prescriber afford it? Economics - cost-effectiveness.
• There are fundamental changes to way prescribers operate - have to protect business interests.

Forward
• Promote access to accurate and complete patient information.
• Apply knowledge regarding drug therapy.
• Monitor drug therapy:
-effective?
-continuing indication? Has complaint been dealt with already?
-ADEs/SE (side-effects).
• Confirming tests before prescribing when possible.
• Standardise products for treating conditions - national guidelines from NICE, but remember: individual variation.
• Prescription not based on industry incentives.
• Improving patient education - explain medication changes - what to expect, written information.

Community pharmacists
• Review inappropriate drugs - check with prescriber.
• Check duplicate prescription eg. if they've been in hospital.
• Check drug/drug and drug/disease interactions.
• Advice on SEs/adverse effects.

Module 2.03

2006-10-01T15:09:00.000Z

The New Open-Access Endoscopy Clinic.
25.9.06 - 6.10.06.

Examination Of The Chest

2006-10-01T15:08:00.000Z

22.9.06

General principles
• Careful and detailed clinical history basis of chest diagnosis (many physical signs picked up during history).
• Methodical and structured chest examination only way to identify important clinical signs.
• Idea that investigations alone can give you diagnosis is false.

Examination
• Look - general inspection.
• Face and neck.
• Hands - clubbed fingers.
• Chest inspection.
• Listening to breathing sounds at mouth.
• Palpation.
• Percussion.
• Auscultation.

Respiratory system as acoustic organ
Pulmonary acoustics
• Percussion of chest.
• Sound of breathing (mouth and at chest wall).

Percussion
• Chest divided into 2 acoustic chambers separated by mediastinum.
• Impulse contains wide spread of frequencies.
• Resonant frequency of chest cavities excited.
• Most useful when there is an effusion.

Breath sounds heard at chest
Laennec's classification
• Breath sounds bronchial and vesicular.
• Added sounds:
-rales;
-rattles;
-rhonchi.

General principles
• Sound and its analysis.
• Sound sources.
• Transmission of sound.

Sound sources
• Airflow through bronchial tree (higher frequency sound).
• Muscles, joints, heart, lung tissue etc. (lower frequency sounds).

Sounds heard at mouth
• Pants.
• Gasps.
• Sighs and yawns.
• Hisses.
• Sniffles.
• Snores.
• Whistles and grunts.
• Stridor.
• Wheezes.
• Rattles.
• Crackles.

Normal lung sounds (originally called vesicular)
• Low frequency.
• Rustling quality.
• Louder on inspiration.
• Vary according to site.
• Some correlation with airflow.

Tracheal sounds
• Higher intensity.
• Inspiration and expiration separated.
• Wider spread of frequencies.

Bronchial breathing
• Occurs when lunch parenchyma airless and supplying lobar airway patent.
• Sounds like tracheal sounds (high frequency).
• Loud, easily heard sounds.

Voiced sounds
• Measuring transmission characteristics of lung.
• "99."
• Muffled in normal lung.
• Easily heard over consolidated lung.
• Whispering pectoriloquy in consolidation.

Lung classification - additional sounds
• Continuous sounds - high-/low-pitched wheezes.
• Interrupted sounds - coarse/medium/fine crackles.

Wheeze
• Sudden onset.
• Frequency does not change with low-density gases.
• Dynamic phenomena.
• Models associated with airflow limitation.
• Continuous musical sound.
• Lasts >250ms.

Types of wheeze
• Random polyphonic wheezes.
• Expiratory polyphonic wheezes.
• Fixed monophonic wheeze.

Crackles
• Very short discontinuous sounds <20ms.
• Usually inspiratory, but also heard in expiration.
• Thought to be due to airways opening.
• Sound is pressure equalisation or sudden.
• Heard from airways close to stethoscope.

Types of crackles
• Fine end inspiratory (<10ms) associated with restrictive lung disease.
• Coarse early inspiratory associated with severe airflow obstruction (COPD) and bronchiectasis.
• Expiratory crackles - severe disease.

Pleural friction rub
• Occurs with friction between 2 inflamed surfaces of pleura.
• Sounds like creaking leather.

Death And Destruction

2006-09-15T18:00:00.000Z

Cell damage, cell death and apoptosis
15.9.06

Cellular injury: causes
• Hypoxia.
• Not the same as ischaemia.
• Physical agencies:
-trauma;
-burns/severe cold;
-radiation;
-electric shock;
-barotrauma.
• Infectious agents:
-cytopathic;
-toxins;
-immune-mediated.
• Other immune reactions:
-autoimmune;
-anaphylactic.
• Nutritional deficiencies/excesses.
• Genetic.

Chemical injury
• Direct eg. acids, alkalis.
-Mercury compounds, cyanide.
• Via toxic metabolites eg. paracetemol.

Cellular injury
• Most vulnerable points:
-mitochondria;
-membranes;
-protein synthesis;
-nuclear DNA.
• Mechanisms.
• Complex, but can be summarised as:
-free radicals;
-ATP deficit;
-mitochondrial damage;
-leaky membranes;
-loss of Ca2+ control.

Free radicals
• Free electron in outer orbit.
• End-point of many processes.
• Highly reactive, chain reaction.
• Generated by:
-respiration ie. metabolism;
-polymorphs;
-transition metal reactions.
• Unpaired electron in outer orbit.
• Very active and propagate.
• Eg. OH•, O2-•, NO2•, NO3-•.
• Implicated in:
-irradiation;
-inflammation;
-chemical and drug injury;
-carcinogenesis;
-ageing;
-paradigm: paraquet.

Cellular injury - outcome
• Minor - recovery.
• Major - apoptosis, necrosis.

Reversible injury
• ATP falls.
• Sodium pump fails.
• Cell swells.
• Anaerobic respiration uses up glycogen.
• If causes uncorrected, leads to…

Irreversible injury
• Severe swelling and disruption of organelles, particularly mitochondria.
• Lysosomes become leaky and enzymes damage cell.
• Can be detected in blood.

Apoptosis
• Dropping off (like leaves) - active process.
• Seen in:
-cell shedding (normal);
-atrophy;
-involution;
-embryogenesis;
-cell injury (insufficient to cause necrosis);
-tumours.
• Programmed cell death.
• Cell dismantled into apoptotic bodies.
• Phagocitised.
• No inflammatory reaction.

Phases of apoptosis
• Signal:
-TNF;
-nuclear cortisol receptors;
-p53-mediated after DNA damage.
• Control:
-fas-fas ligand (CD95 receptor);
-bcl-2 (mitochondrial function);
-increased mitochondrial permeability;
-opposed by bax.
• Effector:
-proteolysis - caspases.
• Removed by phagocytes.

Heart - reperfusion injury
• Free radicals quite low during ischaemia.
• Torrent produced on reperfusion.
• Mainly reactive oxygen species.
• Neutrophils involved (attracted by cytokines).

Treatment For Heart Failure

2006-09-12T14:30:00.001Z

11.9.06

Common causes of chronic heart failure
• Myocardial dysfunction:
-hypertension - asymptomatic;
-IHD;
-cardiomyopathies eg. alcohol.
• Valvular heart disease:
-stenosis - congenital;
-incompetence.
• High output states.

Common causes of acute heart failure
• Acute myocardial dysfunction:
-cardiogenic shock after MI;
-myocarditis.
• Acute valve defects:
-rupture in infective endocarditis.
• Altered rhythm:
-fast - poor filling = low CO = shock;
-slow - low rate = low CO = shock.
• Massive pulmonary embolism.

Left, right or both?
• Distinguish left- and right-sided failure.
• Biventricular failure and left heart failure common.
• Isolated right heart failure less common ("cor pulmonale").

Prevention better than cure
• Detect and effectively manage high blood pressure.
• Smoking, diabetes mellitus and other vascular risk factors.
• Alcohol.

Symptoms of left heart failure
• Chronic:
-dyspnoea, orthopnoea and paroxysmal nocturnal dyspnoea;
-cough and wheeze;
-malaise.
• Acute:
-same, plus…
-symptoms of low blood pressure;
-cough - frothy, pink sputum - haemoptysis.

Signs of left heart failure
• Fine basal crackles.
• Third/fourth heart sound (or both - "gallop rhythm").
• Central cyanosis.
• Low blood pressure, if problem acute.

Symptoms of right heart failure
• Chronic (usually in presence of left heart failure):
-peripheral swelling (dependent parts).
• Acute (eg. after massive pulmonary embolism):
-hepatic pain.

Signs of right heart failure
• Pitting oedema of legs and sacrum.
• Raised JVP.
• Hepatomegaly.
• Ascites.

Prognosis and aims of treatment
• 5-year survival rate with left ventricular failure as bad as many cancers.
• Save life in acute circumstance.
• Relieve symptoms.
• Prolong life.

Differential diagnosis
• Left heart failure:
-asthma;
-pneumonia.
• Right heart failure:
-chronic liver disease.

Initial investigation
• Biochemistry and haematology:
-renal impairment, albumin, thyroid function and haemaglobin.
• Chest X-ray:
-cardiac size, presence of pulmonary oedema/effusions.
• ECG:
-cardiac size and evidence of muscle disease.
• Echocardiography:
-dimensions, valve function.

Drugs for heart failure
• Diuretics.
• Vasodilators.
• Inotropic agents.
• [Beta blockers.]

Loop diuretics: mode of use
• Potent naturesis and diuresis.
• Steep dose-response curve.
• Given IV for acute pulmonary oedema - symptoms may be ameliorated within 30 minutes.
• Given orally (often twice daily) in "maintenance" treatment of congestive cardiac failure.
• Eg. frusemide.

Adverse effects
• Severe dehydration.
• Hypokalaemic metabolic alkalosis.
• Hypomagnesaemia.
• Ototoxicity.
• Hyperuricaemia and gout.
• Decreased glucose tolerance.

Potassium-sparing diuretics eg. spironolactone
• Antagonists of aldosterone.
• Not usually potent enough alone.
• Usually + loop diuretic.
• Reduce mortality (+ACE inhibitor and loop diuretic).
• Adverse effects:
-hyperkalaemia;
-gynaecomastia.

Vasodilators: ACE inhibitors
• ACE converts A1 to A2.
• A2 = arteriolar constrictor.
• A2 increases adrenaline release from adrenal medulla.
• A2 causes aldosterone release (hence, salt retention).
• Lower preload and afterload by blocking synthesis of A2.
• Eg. enalapril.
• No parenteral formulation - used orally in chronic left/biventricular heart failure.
• Adverse effects include:
-renal failure (especially in renal artery stenosis);
-chronic cough;
-hypotension (especially with first dose).

Inotropic drugs
• Most commonly needed after large MI with "cardiogenic shock."
• Low blood pressure, poor renal/splanchnic perfusion; acute renal failure.
• High mortality rate.
• Eg. dobutamine.
• Given IV with very short half-life therefore infusion rate determines plasma concentration.
• Lower infusion rates increase contractility and CO.
• Higher infusion rates: arterial constriction (and tendency to reduced splanchnic perfusion).

Beta blockers
• Negatively inotropic - make CCF worse if used incautiously.
• But, have other actions too (including anti-arrhythmic).
• And reduce mortality in patients on treatment with diuretic and ACE inhibitor.
• Eg. carvedilol.

COPD And Breathlessness

2006-09-12T14:30:00.000Z

11.9.06

NICE definition of COPD
• Characterised by airflow obstruction.
• Usually progressive.
• Not fully reversible.
• Does not change markedly over several months.
• Predominantly caused by smoking.

COPD
• Includes chronic bronchitis and emphysema.
• Characterised by airflow obstruction and little bronchodilator reversibility.
• Normal spirometry excludes diagnosis.
• Prevalence in UK ≈ 1.7% men, 1.4% women.
• 30,000 deaths annually in UK = 6% of all male and 4% of all female deaths.
• By 2020, projected to rank 5th as burden of disease worldwide (12th in 1990).

Impact on services
• >90,000 admissions to UK hospitals per year.
• 10% of all medical admissions.
• Nearly half of all COPD costs are hospital admissions.

Risk factors
1. EXPOSURE TO TOBACCO SMOKE.
2. Others:
• Occupational dusts and chemicals eg. coal dust.
• Specific genetic factors eg. alpha-1-antitrypsin deficiency.
• Indoor and outdoor pollution.
3. Predisposition:
• Recurrent bronchopulmonary infections.
• Socioeconomic status.
• Allergy and airway hyper-responsiveness.
• Lung growth - low birth weight and wheezy bronchitis.

How common?
• 10% females and 11% males have low FEV1 - Health and Lifestyle Survey (1987).
• 9% adult primary care population have abnormal FEV1 and respiratory symptoms - Primary Care Respiratory Journal (2001).
• 27% smokers aged 35-70 with chronic cough have FEV1 <80% predicted - BMJ (2002).
• 37% middle-aged adults who smoked continuously have FEV1 <80% predicted - Locke (2005).

Diagnosis
• Suggested by symptoms/history:
-chronic and progressive cough and/or wheeze and/or shortness of breath (usually exertional);
-impaired ability to exercise;
-significant smoking history.
• Confirmed by spirometry, not peak expiratory flow.
• Spirometry potentially differentiates asthma from COPD.
• If spirometry normal, not COPD.

Respiratory symptoms
• Dyspnoea - all diagnoses, but pattern important in asthma and IHV - episodic and at rest.
• Cough - asthma, ILD - dry; COPD, bronchiectesis - productive.
• Phlegm - COPD and bronchiectesis; frothy, pink with pulmonary oedema.
• Wheeze - any airway disease - asthma, COPD and bronchiectesis.
• Exercise limitation - all diagnoses - consequence of dyspnoea; deconditioning, obesity.
• Haemoptysis.
• Chest pain.

COPD/asthma - history
COPD Asthma
Smoker/ex-smoker Nearly all Possibly
Symptoms under 45 Uncommon Often
Chronic productive cough Common Uncommon
Breathlessness Persistent and progressive Variable

Importance of FEV1/PVC ratio
• Obstructive: ratio <0.7 - asthma/COPD/bronchiectesis.
• Normal: ratio >0.7, <0.8/0.85-ish - asthma/IHV/cardiac disease.
• Restrictive: ratio >0.8/0.85-ish - ILD/obesity.

Other invesetigations
• FBC - Hb and PCV.
• Alpha-1-antitrypsin level.
• ECG - R heart strain, P pulmonale.
• CXR.
• Full pulmonary function, +/- reversibility.
Plus maybe…
• Serial PEF +/- histamine challenge (asthma).
• HRCT (bronchiectesis and emphysema).
• ECHO (heart failure and R heart pressures).

Physiology
• Airflow obstruction.
• Dynamic airway collapse.
• Diffusion abnormality.
• VQ mismatch.
• Shunting.
• Dynamic hyperinflation.

Aims of treatment
• Relief of breathlessness and other symptoms.
• Improve exercise capacity.
• Improve sleep capacity.
• Reduce exacerbations.
• Hence, improve quality of life.

Current COPD treatment
1. All patients:
• Smoking cessation.
• Influenza and pneumococcal vaccinations.
• Short-acting bronchodilators as required.
• Pulmonary rehabilitation if exercise limited.
2. FEV1 <80% predicted:
• All of above, and if symptomatic…
• Long-acting bronchodilators.
• Theopyllines.
3. FEV1 <50% predicted:
• All of above, and if symptomatic…
• Inhaled corticosteroids/combination inhaled steroid/long-acting bronchodilator inhalers.
4. FEV1 30% predicted:
• All of above, and if symptomatic…
• Long-term oxygen therapy.
• Lung transplant.

Exacerbations
• Major cause of mortality and morbidity in hospital admissions.
• UK Audit - ≈ 15% COPD patients dead within 3 months of admission with COPD exacerbation.

Management of exacerbations
• Antibiotics:
-as local protocols;
-culture if failure to respond.
• Oral corticosteroids.

Acute management
• Bronchodilators.
• Corticosteroids.
• Antibiotics.
• Controlled oxygen.
• Ventilations - IPPV/NIV.
• Exercise.
• Home care.

Module 2.02

2006-09-12T14:27:00.000Z

The Tardy Docker.
11.9.06 - 22.9.06.

Treatments For Acute And Chronic Ischaemic Heart Disease

2006-09-06T13:37:00.000Z

4.9.06

Manifestations of ischaemic heart disease
• Sudden death.
• Angina pectoris (1% of entire population):
-stable;
-unstable.
• Myocardial infarction.
• Cardiac failure.

Stable angina - intermittent
• Mismatch of oxygen demand:
-exercise;
-increased ventricular wall tension.
• And supply:
-obstruction - fixed (atheroma), dynamic (spasm) or both;
-anaemia etc.;
-[aortic stenosis].

Treatment of acute attack in stable patient
• Rest.
• GTN - sublingually.
• If not responding quickly, seek help.
• Careful advice to patient about dealing with these episodes.

Chronic treatment of stable angina
• Deal with risk factors aggressively - smoking, hypercholesterolaemia, blood pressure etc.
-aspirin and statins.
• Drug treatment:
-nitrates;
-beta-blockers;
-calcium channel blockers;
-nicorandil.

Nitrates
• Cellular actions - via nitric oxide, nitrosothiols, activation of cGMP.
• Vasodilators:
-venous - decreased venous return, preload - decreased oxygen demand (major);
-arterial - decreased blood pressure, afterload and oxygen demand;
-coronary arteries - increased oxygen supply (minor usually, except in coronary artery spasm).

Adverse effects of nitrates
• Headache.
• Low blood pressure and tachycardia.
• Tolerance - depletion of -SH groups.

Examples and use
• GTN - sublingually (IV), first pass metabolism:
-acute attack/prophylaxis;
-congestive cardiac failure.
• Isosorbide mononitrate (ISMN):
-oral, prophylaxis, often modified release preparations.
• ISDN - oral and IV, angina and congestive cardiac failure.

Beta-blockers
• Block β-adrenoceptor:
-β1 v β2, selectively/nonselectively.
• Used in angina, hypertension.
• Slows the heart, especially during exercise:
-decreases oxygen demand;
-prolonged diastole (when coronary blood flow occurs);
-improves oxygen supply.

Uses of beta-blockers
• Angina.
• [Hypertension.]
• Cardiac arrhythmias.
• After myocardial infarction.
• Congestive cardiac failure.
• Anxiety.
• Thyrotoxicosis.

Examples
• Propanolol - nonselective, lipophilic - liver metabolism.
• Atenolol - selective, hydrophilic.
• [Carvedilol, bisoprolol in congestive cardiac failure.]

Adverse effects
• Bradycardia.
• Peripheral vasoconstriction.
• Bronchoconstriction.
• Rebound - "up regulation" - increased sensitivity to and amount of beta-receptors.
• Congestive cardiac failure.
• Fatigue, depression.

Calcium channel blockers
• Inhibit voltage-dependent calcium channel and decrease Ca2+ entry.
• Reduce smooth muscle contraction.
• Cause vasodilation:
-arterial;
-coronary;
-venous.
• Decreased force of contraction of heart.
• Used in angina and hypertension.

Examples
• Oral, prophylaxis.
• Three classes:
-bind to different, but related, receptor sites - different actions in different tissues;
-nifedipine (dihidropyridines) and relatives - vasodilation, angina, blood pressure;
-verapamil - supraventricular arrhythmias, angina, blood pressure;
-diltiazem - angina, blood pressure.

Adverse effects
• Nifedipine - headache, blood pressure decrease, heartburn, facial flushing, ankle swelling, dizziness.
• Verapamil - headache, dizziness, constipation, heart block, bradycardia.
• Diltiazem - constipation, ankle oedema, flushing, headache.
• All - congestive cardiac failure.
• Interactions - verapamil + beta-blockers - both slow heart, possibly to point of stoppage.

Nicorandil
• Potassium channel opener (mimics calcium channel blockers) and nitrate-like activity.
• Vasodilator.
• ?Other effects??
• Reserve drug for difficult cases.

Choosing a drug
• Aspirin, statins, GTN as required.
• Beta-blockers single best.
• If contraindicated or ineffective, ?calcium channel blocker, ?nitrate.
• Double/triple therapy common.

Invasive treatments
• High-risk patients.
• Patients not controlled with medication.
• Patient preference.
• For most part, no improvements in mortality, but improvement in symptoms.
• PTCA - percutaneous transluminal coronary angioplasty.
• PTCA with stent.
• CABG - coronary artery bypass grafting.

[ST elevation = "tombstone".]

Treatment for STEMI (ST elevation myocardial infarction)
• GTN sublingually.
• Aspirin.
• Pain relief - diamorphine + antiemetic.
• Thrombolysis (early angioplasty?)
-?followed by heparin.
• Antianginals if ongoing pain: beta-blockers and nitrates.

Thrombolysis
• All drugs activate thrombolysis by promoting formation of plasmin from plasminogen.
• Break down fibrin.
• "Golden hour."
• Up to 12 (?24) hours.
• Reduce mortality at 30 days from 12% to 9%.

Thrombolytic drugs
• Streptokinase - short infusion.
• Alteplase - infusion over 90 minutes + heparin.
• Tenecteplase - bolus +heparin.

Hazards
• Anaphylaxis/hypotension (streptokinase).
• Loss of effect, if antibodies.
• Bleeding - intracranial haemorrhage especially.
• Reperfusion arrhythmias.
• Contraindications:
-[prolonged CPR];
-history of bleeding, recent surgery;
-risk of bleeding.
• Excessive bleeding - antifibrinolytics - tranexamenic acid.

Treat complications
• Arrhythmias.
• Congestive cardiac failure.
• Others:
-physical;
-psychological - rehabilitation etc.

Clinical Interpretation Of The ECG

2006-09-06T13:36:00.000Z

4.9.06

Atrial depolarisation + contraction = P wave.
AVN depolarisation = PR interval.
Ventricular depolarisation = QRS complex.
Ventricular repolarisation = T wave.

Iso-electric line represents resting potential of heart.
Positive deflections show electricity flowing towards lead and vice versa.

Assessing ECG
• Rate.
• Rhythm.
• Axis.
• P wave.
• P-R interval.
• QRS complex.
• S-T segment.
• T wave.

• Patient's details.
• Date and time.
• Condition of patient.

• 10 second rhythm strip - usually lead II:
-rate;
-rhythm:
§P wave;
§P-R interval.

Calculating ventricular rate
Eg. 1500 small squares = 1 minute.
R-R interval = 21 small squares.
1500/21 = 71 bpm.

Eg. irregular rate.
25 large squares = 5 seconds.
8 complexes in 25 large squares x 12 = 96 bpm.

Rate
• Tachycardia >100bpm.
• Bradycardia <50bpm. block =" P-R" i =" P-R" block =" No" fibrillation =" No">25% height of accompanying P wave;
-if wider than 1 small square;
-not seen if ischaemia damage does not involve entire thickness of ventricular wall.

Narrow complex tachycardia: impulse passes through AVN.
Broad complex tachycardia: impulse does not involve AVN.

Right bundle branch block
• Right ventricle activated belatedly by wave from left ventricle.
• Can be associated with right-sided cardiac problems:
-chronic lung disease;
-cardiomyopathy;
-atrial and ventricular septal defects.

Left bundle branch block
• Activity in left ventricle delayed.
• Usually indicates underlying cardiac pathology:
-coronary artery disease;
-acute MI etc.

ST segment
• Normal <3>

Module 2.01

2006-09-06T13:34:00.000Z

The Gardener's Funeral.
29.8.06 - 8.9.06.

A new year, a new timetable. Ah, the joys of afternoon lectures and a ridiculously high attendance. Last? I don't think it will...

ABC

2006-06-03T12:31:00.000Z

What happens when you lose everything?
Your breathing, your pulse, your circulation?

Apply compression, you use compressions
Apply compression, you use compressions...

Skin

2006-05-18T10:31:00.000Z

18.5.06

Skin disease is a major and disabling problem for many people all over the world.

Skin
• Largest organ of the body.
• Many different functions:
-Thermoregulations.
-Protection.
-Metabolic functions.
-Sensation.

2 main regions
• Epidermis.
• Dermis.
• Each provides distinct role in overall function.
• Dermis attached to underlying hypodermis (also called subcutaneous connective tissue).
• Superficial fascia of gross anatomy.
• Stores adipose tissue.

Epidermis
• Most superficial layer of skin.
• Provides 1st barrier of protection from invasion of foreign substances into body.
• Principal cell: keratinocyte.
• Subdivided into 5 strata.
• In stratum corneum, keratinocytes migrate to surface and are sloughed off - desquamation.

Stratum germinativum
• Single layer of cuboidal cells - relatively large nuclei - basophilic cytoplasm.
• Only layer where cell division normally occurs.
• Provides germinal cells necessary for regeneration of layers of epidermis.
• Basal cells disivide asymmetrically - 1 daughter cell remain attached to basement membrane.

Stratum spinosum
• Cell in Stratum germinativum accumulate - many desmosomes on outer surface.
• Provide characteristic "prickles" of stratum spinosum ("intercellular bridges").
• Often called prickle-cell layer.

Stratum granulosum
• Keratinisation - accumulation of keratin by progressive maturation of keratinocytes.
• Cekks accumulate dense basopohilic keratohyalin granules.
• Contains lipids.
• Cytoplasm significantly more prominent.
• Nucleus elongated.

Stratum lucidum
• Normally only well-seen in thick epidermis.
• Represents transition from Stratum granulosum to stratum corneum.

Stratum corneum
• As cell accumulates keratohyalin granules - rupture of lysosomal membranes - release lysosomal enzymes - causes cell death.

Dermis
• 2 areas:
-Reticular dermis.
-Papillary dermis.
• Papillary dermis projects as round pegs into overlying epidermis.

Functions of dermis
• Thermoregulation.
• Support of vascular network to supply avascular epidermis with nutrients.
• Consists mostly of fibroblasts.
• Secrete:
-Collagen.
-Elastin.
-Ground substance.
• Gives support and elasticity to skin.
• Immune cells provide defence against foreign particles etc. passing through epidermis.

Papillary dermis
• Contains free sensory nerve endings.
• Meissner's corpuscles in highly sensitive areas.
• Composed of Type III collagen.
• Increase/decrease in blood flow, heat can either be conserved/dissipated.

Reticular dermis
• Consists of dense, irregular tissue.
• Gives skin overall strength and elasticity.
• Includes glands and hair follicles.
• Composed of Type I collagen.

Inflammation and wound healing
Vascular response
• Initial vasoconstriction as direct response to trauma.
• Exposed subendothelial tissue activates coagulation and complement cascades.
• Platelet adhesion and aggregation causes clot formation.
• Degranulation of platelets releases growth factors and chemotactin factors.
• Inflammatory response due to histamine and 5HT release.

Cellular response
• Migration fo neutrophils, macrophages and lyphocytes.
• Macrophages produce growth factors, leading to migration of fibroblast and epithelial cells.

Wound healing
• Epithelial barrier important - prevents infection - maintains fluid balance.
• Achived by both migration and proliferation of epithelia cells.
• Maximum collagen production occurs at 20 days.
• Maximum wound strength at 3-6 months.
• Initial collagen production disorganised.
• Remodelling lines it up with stresses in skin.
• Reduced vascularity and strength.

Scars
• Become red and thickened during healing.
• Takes several months for flattening of wound.
• Excess collagen formation may occur.

Images - Their Clinical Value Post-The Year 1 Assessment

2006-05-18T10:12:00.000Z

16.5.06

Types of image
• Plain films.
• Barium and contrast studies.
• Computed tomography (CT).
• Magnetic resonance imaging (MRI).
• Positron emission tomography (PET).
• Ultrasound.
• Nuclear medicine.

Chest radiographs
Lateral chest X-ray - superseded by CT scans.
Abdomen plain image - psoas major muscle - gluteal muscles.

Contrast studies.
• Injection of suitable medium, into vein.
• IVP - renal excretion.
• T-tube cholangiogram - bile ducts, gall bladder, biliary tree.

Liver - associated blood vessels, porta hepatis.

Contrast studies of bowel.
CTs of abdomen.

Portal system - branches that create portal vein.
Porta-caval system.
Mesenteric vessels.
Mesenteric angiogram.

CT chest.
CT - mediastinal windows.
CT - bony windows.

Lateral skull X-ray.
PA skull X-ray - paranasal sinuses - orbits.

Dentition and eruption dates.

Sagittal T1W MRI brain scan.
Coronal T1W MRI brain scan - ventricles, CSF.
CT of skull.

MRI of abdomen.

Sagittal T1W MRI knee scan.

STIs

2006-05-15T15:04:00.000Z

15.5.06

• Major public health problem on its own, and linking with HIV.
• 75% of curable STIs - developing countries.
• Major causes of morbidity, mortality and health costs - sequelae eg. infertility, CA, AIDS.
• Social and economic upheaval in societies.

What is happening?
• Chlamydia did not exist as bacterial STI until 1960s.
• Improved diagnostic methods.
• Active screening problems.
• People mobility.
• Enhanced surveillance of infectious syphilis was introduced in London in 2001.

Sexual history
• Important competent sexual history and assess risks.
• Non-genitourinary signs.
• Social history.
• Sexual history.
• Contraception.

Common symptoms
• Discharge.
• Rash.
• Lumps.
• Pain.

CHLAMYDIA
• Obligate intracellular small gram negative bacteria.
• Two forms:
-Elementary - infectious.
-Reticulate.

Risk factors
• Age <25 years.
• New sexual partner/more than one sexual partner in recent years.
• Lack of barrier contraception.
• Use of oral contraceptive pill.
• Women undergoing termination of pregnancy.

Asymptomatic in 80% of women and 50% of men.

Treatment of uncomplicated infection
Recommended regimens
• Doxycycline 100mg qd for 7 days.
• Azithromycin 1g orally in single dose.

Alternate regimens
• Erythromycin 500mg qd for 7 days
or Erythromycin 500mg bd for 14 days.
• Or, Ofloxacin 200mg bd or 400mg od for 7 days.
• Or, Tetracycline 500mg qd for 7 days.

Pregnancy and breastfeeding
• Doxycycline and Ofloxacin contraindicated in pregnancy.
• Safety of Azithromycin not fully assessed.
• Erythromycin has significant side-effect profile and <95% effective.
• Amoxycillin 500mg td for 7 days.

GONORRHOEA
• Clinical disease resulting from gram negative diplococcus Neisseria gonorrhoeae.

Recommended treatments - uncomplicated infection
• Ceftriaxone 250mg im.
• Ciproflloxacin 500mg orally as single dose.
• Or, Ofloxacin 400mg orally as single dose.
• Or, Amipicillin 2g/3g plus Probenecid 1g orally as single dose, where regional prevalence of Penicillin-resistant N. gonorrhoeae <5%.
• Or, Cefotaxine 500mg im as single dose.
• Or, Spectromycin 2g im as single dose.

SYPHILIS
Congenital or acquired.

Acquired syphilis:
• Early syphilis:
-Primary.
-Secondary.
-Early latent, <2 years.
• Late syphilis:
-Late latent, >2 years.
-Tertiary gummatous cardiovascular neurosyphilis.

Treatable and curable.

Economics Of Alcohol

2006-05-11T10:09:00.000Z

11.5.06

National burden
• 1 in 20 adults addicted to alcohol.
• 1 in 3 Northern men drink at harmful levels.
• 16-24-year-olds are most likely to be drinking at harmful levels.
• 41% of men and 22% of women in this age group drink above sensible levels.

Local burden
• 1952 patients.
-12.4% attendances to Accident and Emergency.
-9% under age of 18 years.
• Most common reasons for attendance:
-Falls/intoxication.
-Head injury.
-Assault/fight.

Cost to the Trust
• ITU reported to cost 20% of hospital annual operating cost.
• 20% medical admissions related to alcohol.
• Consistent framework for costing yet to be developed.

OTHER COSTS: CASE STUDIES
Case 1: 12-year-old female
• Brought to Accident and Emergency by known prostitute.
• Reported drinking 1 bottle whiskey per day.
• Mother teacher, father accountant, attends good school.
• Resulting harm:
-Medical emergency (choking).
-Child Protection Register.
-STD.

Case 2: 21-year-old female
• 1 bottle whiskey per day since aged 9.
• Sexual abuse by father aged 7.
• Date rape 4 months ago.
• Resulting harm:
-Medical emergency (alcohol withdrawal symptoms).
-Rape.
-STD.
-Homeless.
-?HIV.
-Deliberate self-harm.

Case 3: 76-year-old gentleman
• Drinking 2 bottles sherry per day for many years.
• Evicted from sheltered housing.
• Accused of many petty crimes.
• Resulting harm:
-Chronic unmonitored ill-health.
-Public health risk.
-Probation services.
-Local police.
-Voluntary agencies.

CHALLENGES - Do we have a capsule of despair?

The need to change attitudes
• Whose?
-Society's, as a whole.
• But where do we start?
-Perhaps with our own attitudes and those of our colleagues.

The Alcohol Continuum
Teetotal↔Social↔Hazardous↔Problem↔Dependency

Types of drinker
• Heavy drinker.
• Dependent drinker.
• Problem drinker.

How many units?

Alcohol specialist nurse theory
• Screening for alcohol-related problems.
• Education of doctors/nurses.
• Increase confidence.
• Improve detection rates.

Alcohol specialist nurse practice
• Give support and advice to patients with alcohol-related problems.
• Give support, advice and training to staff caring for patients with alcohol-related problems.
• Advice on medical management of alcohol withdrawal.

Screening and detection of alcohol-related problems
• Prevent consequences of long-term heavy consumption.
• Optimise medical management.

Brief intervention - what are they?
• Limited assessment.
• Advice on changing.
• Materials for self-monitoring and education.
• Setting of goals.
• Motivational interviews for those who are not ready to change.

Factors Influencing Health Of Children And Young People

2006-05-10T15:20:00.000Z

10.5.06

OVERWEIGHT AND OBESITY
• Reduction in physical activity in children has led to obesity.
• Diet also has huge impact - more fast food - high fat, high sugar, less important nutrients - ADVERTISING.

Children 2-10
• 20% overall UK population obese (BMI >30).
• Similar pattern in children.
• Type II diabetes diagnosed in 11-year-olds.
• Children exceeding maximum recommended adult intake.

Obesity and ill health
• Hypertension.
• CHD and stroke.
• Type II diabetes.
• Some cancers.
• Osteoarthritis.
• Mental ill health.

Diet and health
• Up to a third of deaths from cancer and CHD could be prevented by a better diet.
• Eating at least 5 portions of fruit and vegetables each day.

Five a day
• Average UK consumption is 2.8 portions of fruit and veg per day.
• Consumption significantly lower in lower socio-economic groups.
• 20% children eat no fruit.

Diet and health inequalities
• Shopping not done at market/supermarket costs 25% more.
• Healthy diet costs 50% more than unhealthy diet.
• Fruit and veg account for significant proportion of this.

MENTAL HEALTH
Depression in children
• Children - 2-4%.
• Adolescents - 4-8%.
• May present as:
-Behaviour disorder.
-Withdrawn.
-Irritability.
-Uncooperative.
-Disruptive.

Self harm
• Evidence that 10% children self harm.
• Rates now highest in Europe.
• Numbers increased.
• Female:male ratio = 7:1.
• Why do people self harm?

Drug use in last year in 11-15-year-olds
• Illicit drugs:
-Boys - 15%.
-Girls - 13%.
• Smoking:
-Boys - 9%.
-Girls - 12%.

Alcohol consumption (11-15-year-olds)
• Alcohol in last week:
-Boys - 25%.
-Girls - 23%.
• Average consumption per week:
-Boys - 11.6 units.
-Girls - 9.1 units.

Calculating units
• ABV (%) x Volume consumed/1000.

SEXUAL HEALTH
STIs
• 1980s and early 1990s: gradual decline.
• Since 1995, progressive rise.
• Genital warts.
• Chlamydia.
• Gonorrhoea.
• Herpes.
• HIV.

Teenage pregnancy - failure to decline.

The mother
• Single parenthood.
• Educational failure.
• Poverty.
• Unemployment.
• Ill health.

The child
• Increased stillbirth.
• Increased infant mortality.
• More accidents.
• More hospital admissions.
• More likely to live in poverty, to fail in direction, to become teenage parents themselves.

Teenage pregnancy strategy:
• Prevention.
• Support.

CHILD ABUSE
• Physical eg. hitting, throwing, poisoning etc.
• Emotional eg. telling child they're useless, unwanted etc.
• Sexual - physical or non-physical.
• Neglect - withholding food, shelter, clothing, protection from harm.

Prevalence
• 30,000 children on Child Protection Register.
• 600 added each week.
• 25% of rape victims are children.
• 1 child dies each week due to cruelty.

1997 study
• 150,000 children suffer severe physical punishment each year.
• 100,000 each year have potentially harmful sexual abuse.
• 450,000 bullied at school at least once a week.

DOMESTIC VIOLENCE
Definition:
• Physical, psychological, sexual or financial.
• Intimate/family-type relationship.
• Pattern of coercive/controlling behaviour.
• Most victims/survivors women.

Impact on children
• 90% incidents children in same room.
• 25% cases children also subjected to violence.
• 33% children on Child Protection Register have mothers who are victims of domestic violence.

Impact on health
• Immediate result of physical violence.
• Secondary effects of chronic physical and psychological ill health.

Chronic ill health - children
• Frequent appointments.
• Physical injury.
• Vaginal discharge.
• Depression.
• Behaviour problems.
• Sleep problems.
• Enuresis.

NSPCC: 0808 800 5000.
Women's Aid: 08457 023 468.

Society And Lifestyle Choices In Young People

2006-05-09T09:33:00.000Z

9.5.06

Context
• Recent decades have seen numerous changes affecting lives of young people.
• Teenage years commonly viewed as time of peak physical functioning and as being marked by low incidence of illness.

However…
• Increasing evidence shows adolescent physical and mental health related to family structure, own educational attainment, current economical position and personal disposable income.
• Adolescence is a key time when many experiment with behaviours that if they continue will be detrimental to their health.

Smoking and children
• Very few 11-12 year old children smoke.
• By age of 15, 23% children regular smokers in England.

Sociological explanations
• Structural explanation.
-Refers to structures socially constructed or societal structures eg. social class, family, education, gender.
-Focus upon how individual decisions shaped by structures.
• Agency/individual explanations.
-Lifestyle choices made are (in some way) a reflection of who we are and what ewe have seen and done.

Structure and agency/individual explanations
• If we want to understand teenagers' health-relevant behaviours:
-Study within structural locations that influence person/subjective experiences.
-Explore different routes through which young people make transitions towards adulthood.
-Take into account rapid social and economic change occurring.
• Therefore, must take into account BOTH structural and individual explanations.

Pavis et al 2002
• Sought to focus on young people as they made key decisions in life.

Reasons for drinking:
1. For social facilitation.
2. Because of peer influence/pressure.
3. In order to influence mood.
4. For comfort/solace.

Reasons for smoking:
• Type I: smoked solely with one group of friends on in one social setting.
• Type II: smoked with various friendship groups in different social settings.
• Type III: smoked both with different social groups and alone.

Smoker types I and II most likely to give up, as did not view themselves as genuine smokers.

Water Fluoridation

2006-05-08T09:42:00.000Z

8.5.06

Methods of fluoride delivery
• Water fluoridation.
• Fluoride tablets and drops.
• Fluoride salt.
• Fluoride milk.
• Fluoride in fruit juice.
• Topical fluoride applications.
• Fluoride toothpaste.

How does fluoride work?
• Topical and systemic effect - topical effect more important.
• Fluoride incorporated into hydroxyapatite crystals in tooth - renders it more resistant to acid attack.
• Presence in saliva promotes remineralisation of tooth.
• Interferes with metabolic pathways of bacteria, thus reducing acid formation.

History
• McKay.
-"Colorado stain" identified (1901).
-Relationship between stain and caries noted (1929).
• Dean.
-Epidemiology of fluoride, enamel stain and caries (1931).
-Demonstrated inverse relationship between fluoride and caries with reduction at 1 ppm (part per million), and only mild stain at this level (1938).
• Trials in USA of artificially-fluoridated water.
• Trial in UK.
• Fluoridation schemes established in UK in 1960s.

Do we need water fluoridation?
• Prevalence of caries falling.
• Individual behavioural modification lowering caries.
• However, still a problem.

Issues associated with implementing water fluoridation
• Likely positive effects:
-Best available evidence suggest fluoridation of drinking water supply DOES reduce dental caries.
• Likely negative effects:
-Cancer.
-Down's syndrome.
-Bone fluorosis - fractures.
-Alzheimer's.
-Allegation that it may make men frisky.
-Fluorosis.
• Safety of fluoridation:
-Question of possible secondary effects caused by fluorides taken in optimal concentrations through life object of thorough medical investigation - shown to have no effect.
• Ethical issues:
-Autonomy - reduction of individual freedom has to be accepted for greater good.
-Beneficence and nonmaleficence - issues must be considered in terms of whole population.
-Justice - reduces inequalities in health.
• Legal issues:
-Enabling/mandatory frameworks.
-UK - enabling legislation - water companies can choose whether to fluoridate water or not.
-Mandatory - water companies obliged to fluoridate water.
-Water (Fluoridation) Act (1985).
-Water Act (2003).
• Environmental issues.
-No evidence of any adverse environmental effects.
-Chemicals used manufactured as co-product of manufacture of phosphate fertilisers.

Advantages
• Reaches everyone who might benefit from it.
• Cheap.
• 20-40% reduction in caries over a lifetime.
• Safe, cost-effective, consistent, good population coverage, compliance not needed, low risk of overdose.

Disadvantages
• Mass medication.
• Freedom of choice.
• Requires complex infrastructure at beginning and initial capital outlay.

Current situation
• 400 million people worldwide drink fluoridated water.
• 65% of USA population.
• 10% of UK population.

Conclusion
• Decreased caries.
• Cheap and effective.
• Reaches high-risk populations.
• Dental fluorosis at 1ppm very mild.
• Only effective in areas of high caries prevalence.
• Freedom of choice.

Module 1.11

2006-05-08T09:41:00.000Z

Sport And Spots.
8.5.06 - 19.5.06.

Nearly there!

Child Development

2006-05-05T15:40:00.001Z

5.5.06

www.healthforallchildren.com - Parents' page - plot child's growth.

Lines on charts are centiles - based on normal.

50th centile
• 50% of normal children below, 50% above.

2nd centile
• 2% of normal children below, 98% normal.
• Is small child normal or abnormal?

Surveillance about watching (i.e. over time)
• Does child follow centile or cross-centiles?

Sometimes also used as cross-sectional assessment of growth, "screening" separating out those who are probably normal.

Developmental norms are developed empirically.

Regression
• "Given data of a dependent variable y and one or more independent variables x1, x2 etc. Regression analysis involves finding the best mathematical model to describe y as a function of the 'x's."
• Will see it used in many papers.
• Regression used to:
-Describe relationship between variables.
-Predict outcome from set of risk factors.
-"Adjust" for known confounder.
• Interpretation of coefficient depends on model.
• Can be:
-Linear (single or multiple).
-Logistic (probably commonest).
-Proportional hazards.
• Logistic regression estimates odds ratios.
• Will see these terms in papers you read.
• Linear regression different from correlation.

Correlation coefficient: "A measure of association that indicates the degree to which two variables have a linear relationship. This coefficient, represented by the letter 'r', can vary between +1 and -1; when r= +1, there is a perfect positive linear relationship in which one variable varies directly with the other; when r+ -1, there is a perfect negative linear relationship between the variables."

Scenario - notifications?
• Of infectious diseases.
• Commenced end of 19th Century - 1891 in London, 1899 elsewhere.
• List of diseases increased over time - now stands at around 30.
• Originally, head of family or landlord's responsibility to local Proper Officer.
• Now, attending medical practitioner, either in patient's home, surgery or hospital.
• Proper Officer = CCDC.

Purpose of notification
• To detect possible outbreaks of epidemics.
-Accuracy of diagnosis secondary.
• Statistics of collected rationally at Registrar General's office.
• In 1997, responsibility for administering NOIDs system transferred to Communicable Disease Surveillance Centre, now HPA.

Epidemic precipitates investigation, in order to:
• Determine source and mode of transmission.
• Interrupt chain of transmission (control measures).
• Prevent secondary spread.
• Prevent other outbreaks under similar circumstances.

Steps in investigation
1. Confirm diagnosis.
2. Set case definition.
3. Describe case by person, time and place.
4. Formulate and test hypothesis.
5. Undertake any additional methods to control outbreak.
6. Evaluate measures taken.
7. Report on handling of outbreak and its control to various authorities.

Patterns of epidemic
• May start from Common (Point) Source - with all cases exposed at same time to one source of infection.
• In contagious epidemic, disease passed from person to person.
• Slow rise in number of cases.

Prevention paradox?
• Preventive measure bringing large benefit to community, but may offer little to most participating persons.
-Eg. immunisation.
- Why is paradox problem for NHS?
• People motivated by benefit which is visible, early and likely.

Infectious disease epidemiology
• Health promotion.
-Disease prevention.
§Primary - immunisation.
§Secondary - limiting spread.

Gait

2006-05-05T15:40:00.000Z

4.5.06

Gait control
• Cortex, pyramidal.
• Cortex, extra-pyramidal.
• Cerebellum.
• Reflex arc - can be tested.

Development of walking
• Milestones.
• Development of all structures required.
• Characteristic patterns when impaired.

Milestones
• Sits at 6 months.
• Crawls at 9 months.
• Stands and walks aided at 15 months.
• Walks unaided at 15 months.
• Runs at 18 months.
• Adult pattern by 3 years.
• Fully mature pattern only by 6 years.

Infant gait pattern
• Jerky, unsteady, wide-based.
• Arms abducted and extended.
• Foot-strike flat and knee flexed.
• Longer double stance phase.
• Rapid steps, but low velocity.

What can go wrong?
• Brain.
• Spinal cord.
• Nerves.
• Muscles.
• Joints.
• Bones.

Brain
• Cortex and internal capsule.
-Stroke - usually one-sided.
• Extrapyramidal system.
-Parkinson's.
• Cerebellum - important in coordination of gait.
-Ataxias.

Spinal cord
• Injuries.
• Tumours.
• Degeneration.

Upper and lower motor neurones
• Upper motor neurone lesion.
-Increased tone and reflexes.
-Spastic paralysis.
• Lower motor neurone lesion (anterior grey horn).
-Decreased tone and reflexes.
-Flaccid paralysis.

Nerves and muscles
• Injuries.
-Laceration, traction.
• Pressure.
-Carpal tunnel syndrome.
• Degeneration.
-Polio, motor neurone disease, myopathies.

Bones and joints
• Injuries.
-Fractures, ligament ruptures.
• Degenerations.
-Osteoarthritis.

Gait analysis
Normal gait
• Gait cycle.
• Stance phase.
• Swing phase.
• Double stance.
• Double swing.

Some abnormal gaits:
• Painful gait (antalgic) - short stance phase.
• Drop foot gait - rupture of tibialis anterior, L5 root problem.
• Parkinsonian.
• Cerebellar.
• Stiff leg gait - joint abnormalities.
• Athetoid - wild, abnormal movements.
• Back-knee gait.
• Tabetic - heavy walk - no sensory input from feet - syphilitic loss of proprioception.
• Spastic diplagic - scissor gait.
• Stroke (paraplagic).
• Lurching (rolling) gait - hip pathology.
• Trendellenburg.
• Slapping gait - less pronounced version

Appropriate And Inappropriate Attitudes In Healthcare

2006-05-03T17:51:00.000Z

3.5.06

What are morally inappropriate attitudes?
• Attitudes aimed at (in)appropriate objects.
• Attitudes aimed at appropriate objects, but had to (dis)proportionate degree.
• Attitudes expressing (in)appropriate attitudes.

Examples of appropriate attitudes:
• Empathy.
• Sympathy.
• Appropriate/proportionate feelings of anger.
• Degree of modesty/humility.
• Appropriate sense of fun?

Examples of inappropriate attitudes:
• Callousness.
• Racist, sexist, ageist and other prejudicial attitudes.
• Senseless/disproportionate anger.
• Pleasure felt at another person's displeasure/suffering.
• Inappropriate amusement.
• Excessive anxiety.

Two types of cases in which in which inappropriate attitudes may raise fitness to practice concerns
1. Where attitude threatens to negatively impact on behaviour/practice:
(i) By causing distorted/inadequate understanding of features of clinical situation.
(ii) By affecting motivation.
2. Where attitude itself is source of harm - where this may be a result of:
(i) The offence caused by the showing of that attitude.
(ii) The negative effect that attitude has on the patient-doctor relationship, and thereby the quality of car the patient is likely to receive.

Points of consideration:
1. Potential harm threatened by possession of attitude should be sufficiently severe in order to cast doubt on practitioner's fitness to practice.
2. Mitigating circumstances exist in which having of the attitude not to be taken as good indication of practitioner's overall fitness to practice.
3. How might we go about cultivating the right attitudes in ourselves and others?
-Are attitudes things that we can simply change at will?
-Might not be clear.
-May have some direct control over behaviours that will eventually impact on attitudes we have.
4. Issue of responsibility.
-Attitudes involuntary, therefore, should not be held responsible for them.
-May have some control over whether we cultivate certain attitudes in ourselves.
-Therefore, sometimes indirectly responsible for attitudes.
-People who feel wrong attitudes should not always be reproached for those attitudes.

Questions
1. In what ways do you think attitudes may impact on behaviour?
2. How do you think we can cultivate better attitudes in ourselves?
3. Do you think we should ever be punished/reproached for having certain attitudes?

Further reading
• "Tomorrow's Doctors" - GMC (2003).
• "Learning Outcomes For Attitudes, Ethical Understanding And Legal Responsibilities" - Scottish Doctor.

Analgesic Drugs

2006-04-28T16:04:00.000Z

28.4.06

Not covered:
• Opiates.
• Disease-modifying drugs for rheumatoid arthritis.
• Drugs for neuralgic pain.

Pain
• Somatic.
-Inflammation of epithelial surfaces, trauma, sepsis.
-Felt at site of pathology.
• Visceral.
-Eg. myocardial ischaemia, colic.
-Poor localisation, often "referred."
• Neurogenic.
-Eg. neuralgia.
-No response to analgesics.

Osteoarthritis
• Common.
• Disease of cartilage.
• Big weight-bearing joints: knees and hips.
• More likely if there is joint insult eg. trauma.
• Congenital component: "primary familial osteoarthritis."
• Heberden's nodes, distal interphalangeal joints.

Rheumatoid arthritis
• Common.
• May commence at any age.
• Inflammatory condition: joints commonest "tissues" involved, but also inflames arteries etc.
• Small joints: hands and feet.
• Hands: metacarpal phalangeal joints and primary interphalangeal joints.

Gout
• Common.
• Paroxysmal arthritis, with quiet joints between attacks.
• Any joint, excepting axial skeleton.
• Uric acid crystals in joint fluid.
• Most commonly, first metatarsal phalangeal joint.

Ankylosing spondylitis
• Less common.
• Around 20% people with HLA B27.
• Low back pain in early 20s, leading to variable degrees of spinal deformity.
• Also, arthritis of hips and knees.
• Other tissues: iritis.

DRUGS
Paracetemol
• Mechanism pf analgesic activity not fully understood: ? decreased prostaglandin synthesis in CNS.
• Mechanism of antipyretic activity: decreased PG-E2 in hypothalamus.
• Safe, effective analgesic used OTC:
-Analgesia.
-Lowering elevated temperature.
-No anti-inflammatory effect.
• Dangerous in overdose.
• Main problem: hepatotoxicity.
• Takes around 24-36 hours to become apparent.
• Antidote: n-acetyl cysteine, but use in first 24 hours.
• Damage correlates with paracetemol concentration.
• Measure concentration - no earlier than 4 hours.

NSAIDs
Aspirin
• Acetylsalicyclic acid.
• Analgesic/antipyretic at low dose.
• Anti-inflammatory at high dose.
• [Anti-platelet activity at low dose.]
• Upper GI irritation and bleeding.

Aspirin overdose
• Partly eliminated unchanged in urine.
• Strong acid, lipid soluble at acid pH (remember Henderson-Hasselbach).
• "Alkaline diuresis": iv bicarbonate to yield alkaline urine.
• Hence, water soluble aspiring and higher aspirin clearance.
• Dialysis in most serious cases.

Other NSAIDs
• [Ibuprofen: OTC as analgesic.]
• Naproxen.
• Diclofenac.
• Useful in inflammatory arthritis.
• Use adjunct to opiates in terminal care.

COX-II inhibitors
• Anti-inflammatory, useful for Rh-D.
• Much more expensive than older NSAIDs.
• Reserve for selected patients with PUD or GORD.
• Rofecoxib withdrawn for SAEs - may prove to be class effect.

NSAID adverse effects
• GI.
• Salt and water retention.
• Renal impairment.
• Asthma may be precipitated.

DRUGS FOR GOUT
Acute gout
• Commonly precipitated by diuretics (especially thiazides).
• May be very severe and resemble septic arthritis.

Treatment
• Rest.
• NSAID until arthritis settles.
• Worst cases merit prednisolone.
• If prophylactic drug (eg. allopurinol) to be used, then NSAID "cover."

Allopurinol
• Purine bases metabolised via xanthines to uric acid.
• Xanthines water soluble.
• Uric acid pretty insoluble.
• Allopurinol inhibits xanthine oxidase.
• Used to decrease frequency of paroxysms.
• May precipitate acute gout when first started: NSAID "cover."

Acute drug reactions and interactions
• GI upset.
• Rash.
• Azathioprine - potentiated.
• Warfarin - potentiated.

The Rise Of The "Nanny State"

2006-04-27T10:29:00.000Z

27.4.06

• Increasing state responsibility for health.
-Vaccination.
-Health of infants.
-Health "protection" and "promotion."
• Risk and responsibility in health.

Why introduce state medicine?
• Threat theory.
-Provoked by epidemic diseases - cholera.
-"Urban penalty" of high mortality rates.

Contagious Diseases Acts
• Passed in 1864, 1866, 1869.
• Women with disease could be detained and forcibly treated.
• Acts suspended in 1883, repealed in 1886.

Compulsory Disease Notification
• 1889 Act.
• Permissive, not compulsory.
• Limited to certain infectious diseases.
-Smallpox, diphtheria, scarlet fever, typhoid.
-Later, tuberculosis.

• Improvement theory.
-Fear of national deterioration.
-Increasing competition with German and USA.
-Poor health of Boer War recruits.
-1904 - Report on Physical Deterioration.

19th Century medical care
• Piecemeal, un-integrated network.
• Three types of hospitals.
-Voluntary (including cottage).
-Poor Law.
-Municipal (isolation).

• Primary care.
-Private physicians for wealthy.
-Dispensaries for working classes.
-Increased use of friendly societies, clubs.

Health visiting
• Voluntary middle class movement.
• Salford - 1870s.
• Targeting mothers.

Political pressure
• Enfranchisement of working classes (and women!)
• Rise of Labour Party.

Liberal Welfare Reforms
• 1905-1911 - "a welfare state in embryo."
• School medical service.
• Free school meals and milk.
• Infant and maternal welfare clinics.
• Health visiting.
• 1911 - National Health Insurance Act.
• Established panel doctors (state paid).
• Only covered working men.
• Limited medical treatment.

Enough to eat?
• 1930s.
• Evidence of malnutrition in working class communities.
• Government attitude.
• Politicisation of health research.

1948 - new expectations
• 5 July 1948 - formation of NHS.
• Further shift in responsibility from individual to state.

Role of medicine
• Central to new NHS.
• Aneurin Bevan's attitude to engaging doctors: "If necessary, I will stuff their mouths with gold."

Smoking and lung cancer
• 1950s.
• Richard Doll and Austin Bradford Hill.
• Study of doctors' smoking habits.
• Government response.

Duty to inform?
• 1962 - Royal College of Physicians report on smoking and health.

Duty to promote?
• Exercise and healthy eating.
• Family planning.

Duty to protect?
• Public expectations.
• 1970s whooping cough vaccine problems.
• AIDS.
• BSE.
• Passive smoking.

Community Perspectives On Early Childhood Development

2006-04-26T17:31:00.000Z

26.4.06

There was also a handout to go with. The notes below are just the slides that weren't included on the handout.

Why screen children?
• To detect remedial condition.
• To check growth.
• To check developmental milestones reached.
• To support parents - give information, address concerns.
• To address public health issues.

Neonatal examination
• Hospital-based, within first 24 hours.
• Check weight and head circumference.

Major disorders
• Down's syndrome (1 per 600).
• Congenital hypothyroidism (1 per 5,000).
• Phenylketonurea (1 per 13,000).
• Congenital heart disease (7 per 1,000).
• Congenital dislocation of the hip (1 per 1,000).
• Undescended testes (60 per 10,000).

6-8 week check
• Done by GP in specific baby clinics.
• Developmental milestones.
• Measure and plot weight, length and head circumference.
• Top-to-toe examination.
• Ask about parental concerns and address issues.
• Discuss feeding, parental coping, smoking, prevention of cot death, immunisations.
• Screen for post-natal depression.

6-9 month check
• Done by health visitor.
• GP only involved if problems.
• Looking for:
-growth;
-squint - cover test;
-hearing - distraction test;
-developmental milestones.
• Check for parental concerns.
• Ask specifically about hearing and vision concerns.

3 year check often by questionnaire.

5 year check
• Done by school nurse.
• Children with special educational needs - followed up annually.

Growth problems
Failure to thrive:
• Failure to gain weight at normal rate.
• Commonest cause: inadequate dietary intake.
• Further investigation - CF, coeliac disease.

Short stature:
• Short parents = constitutional short stature.
• Height below 3rd centile.
• Causes: chromosomal abnormalities, poor gestational nutrition etc.

Normal hearing
• Not turning to sound <6 months old.
• Ignoring being called at 3-4 years.

Walking
• Normal late walking up to 18 months.
• Often familial.
• Bottom shufflers - 10% of population - often familial.
• Hypotonia.

Referrals to community paediatric units
• Hearing problems.
• Speech and language problems.
• Visual problems.
• Developmental delay.
• Behavioural/psychological problems.

Important issues to cover in child health promotion clinics
1. Immunisations
• Explore parental attitude to immunisations.
• Address parental concerns.
• Check immunisations up-to-date.

2. Universal advice
• Cot death prevention.
• Smoking cessation etc.

3. Parental issues
• Contraceptive advice.
• Post-natal depression screening.
• Support of good parenting skills.
• Parental concerns.

4. Child protection issues.
• Four types of abuse:
(i) physical;
(ii) emotional;
(iii) neglect;
(iv) sexual.
• Watch out for:
-mental health problems of carers;
-previous history of neglect;
domestic violence.

If child abuse suspected
• Consider whether child needs immediate removal.
• Other cases: refer to social services.
• Patient confidentiality can be breached in child's best interests.

Cystic Fibrosis: From Laboratory To The Clinic

2006-04-25T15:40:00.000Z

25.5.06

Short history
• Dorothy Andersen - pathologist with special interest in children - carried out post-mortems on children - start of last century - coeliac disease (gluten insensitivity) - found not coeliac disease: "cystic fibrosis of the pancreas" - associated respiratory symptoms.
• Paul di St Agnisi, 1950s New York City.
• High sweat salts - drawing on Medieval folklore - became diagnostic test for CF - pylocarpin applied topically and charge applied to stimulate sweat glands.
• Holistic care:
-chest;
-nutrition;
-social.

Why do children with CF have problems with chest infection?
• Salt transport.

CFTR gene makes ion-transporting protein pore - pores situated in apical surface of epithelium. Lungs sterile due to "mucosillary escalator" - cilia - periciliary aqueous layer helps cilia to beat - mucous layer on top of this - absorbing liquid in respiratory epithelium via sodium transport (ENaC) - water pulled through via osmosis.

CFTR protein:
• 12 transmembrane domains.
• Large R domain.
• 2 NBFs.
• Cl- out of cell, Na+ into cell through difference channel.
• CFTR not Na+ - only regulates Na+ channel - acts as brake on Na+ channel.
• No CFTR protein in CF - lose brake on Na+ channel - increased Na+ absorption - dehydrated periciliary aqueous layer - cilia clamped down - problem with mucosillary clearance.
• Body can form mucosillary transport through other mechanisms - more mucous formed, but becomes dehydrated also - prime breeding ground for bacteria - form chronic infection.

• Difficult bacteria.

• Inflammation - neutrophils enter lungs and become stuck in mucus - explode - release lots of DNA - very sticky.

Paediatric clinic
• Multi-disciplinary team.
• CF nurse specialist.
• Dietician.
• Physiotherapist.
• School teacher.
• Social worker - disability living allowance.
• Psychologist.
• Physicians.

Hope 1: ion transport modulators
• Amiloride - clinical trials - only works for 30 minutes.
• Long-acting Na+ channel blockers.
• Chloride secretagogues.
• Problems:
-dynamic;
-early;
-mucus.

Hope 2: gene therapy
• Somatic gene transfer.
-Replication-deficient viral vector.
§Integrating.
§Non-integrating.
-Liposome vectors.
• Systemic gene transfer.
• Stem cell.
• Foetal gene transfer.

Hope 3: modulators of inflammation
• Steroids.
• NSAIDs - ibuprofen.
• Azithromycin.
• Newer compounds.

Module 1.10

2006-04-25T15:39:00.000Z

Going to Nursery School.
24.4.06 - 5.5.06.

Functional Significance Of The Mouth

2006-04-03T09:48:00.000Z

31.3.06

The oral cavity
Tissues
• Bone.
• Joint(s).
• Epithelia.

Borders
• Lips.
• Palatoglossal fold.
• Palate.
• Cheeks.
• Floor of mouth.

Lips
• Muscular structures.
• Non-keratinised oral mucous membrane.
• Angle of mouth.

Cheeks
• Muscular structures.
• Non-keratinised oral mucous membrane.
• Buccinator muscle.

Tongue
• Dorsum.
• Ventral (inferior) surface.
• Lateral borders.

Dorsum of tongue
• Anterior two-thirds - sensory (V), taste (VII).
• Posterior one-third - IX.

Tongue muscles
• Extrinsic - genioglossus, hyoglossus, palatoglossus.
• Intrinsic - superior longitudinal, inferior longitudinal, vertical, transverse.

Functions
• Mastication.
• Speech.
• Taste.
• Oral hygiene.
• Communication (gestures).
• Sensory (infant).

Hard palate
• Maxilla and palatine bones.
• Thick keratinised epithelium.

Soft palate

Salivary glands
• Minor salivary glands - everywhere.
• Major salivary glands.
-Parotid (25% - mainly serous).
-Submandibular (70% - mixed saliva).
-Sublingual (5% - mainly mucous).

Muscles of mastication
• Temporalis.
• Masseter.
• Medial pterygoid.
• Lateral pterygoid.
• Accessory muscles of mastication.

Temporomandibular joint
• TMJ = synovial joint with intervening disc.
• Disc divides joint ccavity into 2.

Nerve supply to muscles of mastication
• All V apart from buccinator (VII).

Nerve supply to oral cavity
• V (trigeminal).
-Ophthalmic branch.
-Maxillary branch.
-Mandibular branch.

Blood supply to oral cavity = internal carotid and its branches.

Saliva
Protective functions
• Lubrication - mucins, glycoproteins, water.
• Antimicrobial.
-Amylase - breaks up starch.
-Complement.
-Lysozyme.
-Secretory IgA.
• Contains growth factors - healing.
• Maintains mucosal integrity.
• Lavage/cleansing/clearance of sugars and acids.
• Buffering.
• Remineralisation.

Food- and speech-related functions
• Food preparation - water, mucins.
• Digestions - amylases.
• Taste.
• Speech.

Considerable volume produced each day: 0.5-0.75l.

Salivary gland anatomy

Secretory unit
• Acini.
• Ducts.

Parotid gland
• VII branches divide gland into superficial and deep lobes, while moving from stylomastoid foramen to muscles of facial expression.

Salivary constituents
• Ions - Na+, K+, Ca2+, PO4-, Fl-, Cl-.
• Miscellaneous.
-Blood and blood-derivative compounds.

Factors contributing to saliva content
• Normal human variability.
• Unstimulated versus stimulated saliva.
• Ageing (not per se, but medications of ageing do).
• Medications - 500 that cause dry mouth (xerostomia).
• Disease.
• Circadian rhythms.

Factors affecting salivary production
• Local diseases.
• Systemic diseases.
• Medication.

Salivary dysfunction and oral sequelae
• Dental caries.
• Mucositis.
• Oral ulceration.
• Taste.
• Swallowing.
• Dentures - loose and painful.
• Infections.

Dental anatomy
Human dentition
• 32 permanent, 20 primary.

Incisors
• Straight edges.
• Designed to cut through food.

Canines
• Function: pierce and hold food.
• Located at corners of mouth.

Premolars
• Some characteristics of both canines and molars.
• Located between canines and molars.

Molars
• Crush and grind food.
• Located at back of mouth.
• First, second and third molars.

Tooth surfaces
• Proximal.
• Lingual.
• Facial.
• Incisal/buccal.

Enamel
• Covers crown.
• Hardest substance in human body.
• Highly mineralised.
• Brittle.
• After initial completion, new enamel cannot be formed.

Dentine
• Largest component of tooth.
• Contributes to tooth colour.
• Can form throughout life - reparative dentine.
• Structure: dentinal tubules.

Cementum
• Covers root.
• Formed continuously throughout life.

Dental pulp
• Soft tissue.

Supporting structures (periodontium)
• Cementum, periodontal ligament, gingivae, alveolar bone.

Dental x-rays
1. Bitewing - check for dental caries in back teeth.
2. Periapical - whole-tooth radiograph.
Panaramic view (orthopantomogram - OPG) - plan view of all teeth - MOST IMPORTANT.

Formation of teeth
• Entire primary dentition begins at 6-8 weeks in utero.
• Successional secondary dentition begins at ≈20 weeks in utero.
• Stages of crown development.
• Dental lamina/tooth bud.
-Extends in from lamina.
-Enamel organ formation - will mineralise.
-Cap stage.
• Initial amelo- and dentinogenesis.
• Ameloblasts and odontoblasts.

Tooth eruption dates

And bytheway, I have complete faith in Paul Collingwood.

Foetal circulation

2006-04-03T09:47:00.000Z

30.3.06

Cardiovascular system
• Vasculogenesis.
• Early circulation.
• Foetal circulation.

Vasculogenesis
• Day 17.
• Wall of yolk sac.
• Splanchopleuric mesoderm form aggregations of cells.
• Blood islands.
-Core of haemoblasts.
-Surround of endothelial cells.
-Haemoblasts - embryonic blood cells.
-Endothelial cells - blood vessel endothelium.
-Blood vessel endothelia elongate.
-Interconnected mesh.
-End week 3: vascular network around yolk sac, connecting stalk and chorionic villi.
• Angioblastic cords - throughout germ disc.
• Angioblastic plexuses.

Growth of circulatory system
• Continued formation and fusion of angiocysts.
• Angiogenesis - budding and sprouts of new vessels.

Cardiogenic area

Heart development
• Two tubes.
• Fusion.
• Single chamber.
-Sinus venosus.
-Atrium.
-Ventricle.
-Bulbus cordis.
-Truncus arteriosus.
• Chamber elongates - restricted by volume of primitive pericardial cavity.
• Develops kink.

Circulation
• Blood from placenta → primitive heart → dorsal aortae → umbilical arteries → tertiary villus → umbilical veins → sinus venosus → primitive heart.
• Vitelline vessels give rise to portal vein.

Placental structure
• Blood pumped in spurts into intervillous space.
• Vessels on maternal side separate entities that pump maternal blood to placenta.
• Branches increase surface area - each branch contains mesh of capillaries.
• Embryonic tissue forms septa - strengthen placenta (cotyledons) - seen on maternal side.

Foetal haemoglobin - hypoxia countered by
• γ chains in haem.
• Carry more O2 - greater affinity for O2.
• 180gl-1.
• Greater cardiac output.

Umbilical cord
• Begins as connecting stalk.
• 2 arteries, 1 vein (right umbilical artery disappears).
• Set in gelatinous substrate - mucoid connective tissue.
• → ductus venosus.
• Bowels herniated into umbilical cord, then come back into abdomen later in development.
• Umbilical vein → north towards liver → shortcut: ductus venosus → inferior vena cava.

Veins

Portal vein

Bilateral symmetry and regressions
• Arterial system - regresses on right.
• Venous system - regresses on left.

Limb vessels
• Primary - axial artery.
• Axial artery rearranged into minor vessels.
• Secondary vessels form major vessels - new development from primary vessels.

Arch arteries
• Trucus arteriosus → 6 arch arteries (number 5 doesn't develop in humans) → aortic trunk → divides into 2 flows.
• Give rise to adult vessels.
-IV and VI important.
-I = maxillary artery.
-IV = arch of aorta on left, subclavian on right.
-VI = ductus arteriosus on left (shunt between pulmonary circulation and systemic circulation).

Foetal circulation
• IVC.
• Right atrium.
• Foramen ovale (shunt between right and left atria).
• Left side.
• Head and brain.
• Right side.
• Pulmonary trunk.
• Ductus arteriosus.

Infant circulation.

Auscultation.

Introduction To Antibiotics

2006-04-03T09:46:00.001Z

27.3.06

What?
• Compounds that act against bacteria (antimicrobials - against parasites, fungi).
• Kill (bacteriocidal) or inhibit (bacteriostatic) - not useful distinction nowadays.
• Administered orally, parenterally or topically.
• Resistance may rapidly develop.

Complex relationship
• Drug ⇔ [potency versus resistance] ⇔ Bug.
• Bug ⇔ [virulence versus immunity, attack versus defence] ⇔ Host.
• Host ⇔ [metabolism versus toxicity] ⇔ Drug.
• Balance makes outcome good or bad.

How are bacteria classified?
• 2 ways - colour on staining or shape.
• Gram staining - gram + (purple) or gram - (pink).
• Shape - coccus (round) or bacillus (rod).

Some medically important bacteria
Gram +
• Cocci (generally throat).
-Staphylococcus.
-Streptococcus.
• Rods.
-Clostridia - cause of antibiotic diarrhoea - antibiotics kill colonic flora and new ones recolonise.

Gram -
• Cocci.
-Neisseria - neisseria meningitidis causes meningitis, neisseria gonorrhoea.
-Haemophilis - also slightly bacillus with capsule - more virulent - meningitis in <4 years, swells without capsule, troat infection, epiglottis - HiB vaccine, haemophilius, influenza B vaccine - capsule.
• Rods - generally gut/abdomen.
-E. coli.
-Proteus.
-Klebsiella.
-Salmonella.

• Important: gram + cocci and gram - rods.
• Anaerobic bacteria - strep faecalis etc.
• Human bites dirtier than dog bites.
• Staphylococcus aureus - boils - druggies get most often.

Infections
Is there infections? Take culture. Fever? Pain, swelling, redness, tachycardia, sweats, pus, toxaemia.

Where is site? What are likely organisms?

What antibiotics are likely to be effective?
• β lactams.
-Penicillins (amoxycillin, flucoxacillin, benzylpenicillin)
-Cephalosporins (cephtriaxone).
-Others.
• Aminoglycosides.
-Gentamycin.
• Macrolides.
-Erythromycin, clarithromycin.
• Quinolones.
-Ciprofloxacin against gut rot/diarrhoea.
• Tetracycline.
• Glycopeptides.
• Metronidazole.

Is there likely to be resistance?

Will the antibiotic penetrate to the site?

Route of administration?

What is the toxicity and cost?

Likely resistance?
• Community acquired or hospital acquired?
• Previous antibiotics?
• Travel history?
• Nasocomial infections - hospital acquired - tend to be resistant eg. MRSA, clostridium difficile.
• Preventable - hygience, antibiotic control.
• Broader spectrum used.

Penetrating to site? Route? Consider
• Very sick?
• Serious infection?
• Barrier to drug absorption?
• Malabsorption - post-surgery?
• Vomiting or swallowing problems?
• Poor bioavailability.

Common mistakes
• Often not effective.
-Tonsillopharyngitis (viral).
-Gastroenteritis (self-limiting usually).
-Colonisation versus infection.
• No prior culture obtained.
• Inappropriate dose/route.
• Continued for too long.

Change And Choice In Childbirth

2006-04-03T09:46:00.000Z

24.3.06

• Places of birth and choices of support.
• Medicalisation of pregnancy and childbirth.
• Maternal mortality - the silent crisis.
• Choice and rights.

Changing place of birth
• 1927 ~ 85% home births.
• 1961 ~ 32% home births.
• 1980 ~ 1.3% home births.
• Hospital birth increasingly synonymous with "safe birth."

Man-midwives
• Exploiting medical knowledge.
• AKA "accoucheurs."
• William Smellie (1733-1815).
• 3 stages of labour.
• Rise of the surgeon - apothecary - general practitioner.

18th Century
• 1730s - increased use of forceps.
• More anatomy, physiology and pathology knowledge.

But…
• Limited obstetric teaching.
• No successful caesareans before 1890s.
• Despised by physicians and surgeons.
• No Royal College of Obstetricians until 1929.

Reducing the risks of childbirth
• James Young Simpson - anaesthesia in childbirth 1849.
• Queen Victoria's "blessed chloroform" 1851.
• Management of complications.
-Placenta praevia.

Puerperal "childbed" fever
• Streptococcus pyogenes.
• Ignaz Semmelweis (1818-65).
• Vienna Maternity Hospitals.
• Proved medical students carried infection to maternity wards from mortuary.
• Introduced carbolic hand wash.
• Semmelweis ridiculed.
• Louis Pasteur (1822-95).
• Joseph Lister (1827-1912).
-Antisepsis technique.
• Single Causation theory.
• 1880s - obstetric antiseptic practice.

Medicalisation of childbirth
• Increased use of anaesthesia.
-"Twilight sleep" fiasco.
• Western women "all have difficult labours."
• GPs applied forceps under general anaesthetic in 50% of normal deliveries.
-For doctor's convenience?

The backlash?
• Grantley Dick Read (1890-1959).
• "Natural Childbirth" published 1933.
• Stressed the "psychosomatic" as opposed to "mechanistic" approach.
• "Fear-tension-pain" syndrome.
• Advocated more relaxation and less drugs.

Professionalisation of midwifery
• Pre-20th Century image: "drunken old hags."
• 1902 Midwives Act.

Maternal mortality
• 1890s ~ 13 maternal deaths a day.
• 1990s ~ <1 maternal death a week.
• 1920-1929 ~ 25,000 maternal death in UK.
-Puerperal infection, toxaemia, haemorrhage.

Statistical black spot - Rochdale
• Most dangerous place in Britain to give birth in 1930.
• 90 maternal deaths per 10,000 deliveries.
• Government inquiry.

"Magic bullets"
• Gerhard Domagk (1895-1964).
• 1935 - developed first sulphonamide.
-Prontosil.
-Led to almost 100% recovery from puerperal fever.

Reversing the trend
• Ergometrine.
• Blood transfusions.
• Penicillin (1945).
• NHS (1948).
• Improved medical education.

Liverpool's contribution
• Robert Minnitt (1889-1973).
-Developed self-administration of obstetric anaesthesia "gas and air" machine.

New issues
• Increasing rates of medical intervention.
• Episiotomy rare before 1970s.
• Caesarean rates.
-1950s ~ 2%.
-2000s ~ 20%.
• Screening and monitoring.

Birth, The Neonate And Growth

2006-04-03T09:45:00.000Z

Another of Dangerfield's.

23.3.06

• Pregnancy.
• Skull shape.
• Anthropometry.
-Techniques.
-Growth charts - centiles.
-Longitudinal growth charts.
• Scoliosis.
• Influence of parents.

Growth variations of foetus
• Smoking.
• Poor nutrition/poverty.
• Diabetic mother.
-Obese child, but soon normalises.
• Low birth weight.
-Preterm versus light for dates.
• Poor lactation and failure to thrive.
• Neglect.
-Abuse.
• Hospital.

• Bone growth.
• Ossification.
• Growth plate.
• Foetal skull.
• Foetal skeleton.

• Ability.
• Motor development milestones.
• Walking.
-Gluteus maximus (gluteal region).
-Ilio-tibial tract.
-Upper outer quadrant for IM injections.
-Achilles tendon.
-Calf.
• Reflexes.
-Grasp.
-Moro.
-Stepping.
• Bony landmarks.
-Bones of forearm.
-Extensors of forearm.
-Surface markings of hand.
-Surface landmarks of wrist.
• Growth influences: hormones.
• Determinants of growth/determinants of health.

"Mothers, Babies and Disease in Later Life" - Barker.

Birth And The Post-Natal Period

2006-04-03T09:44:00.000Z

22.3.06

"Childbirth itself is a natural phenomenon, and the large majority of women need no interference whatsoever - only close observation, moral support and protection."
-Klooserman, 1972.

Antenatal
• Scans.
• Clinics.
• Groups.
• Birth plan.
• Waiting.

Onset of labour
• Spontaneous rupture of membranes.
• Cervical changes.
• Change in contractions.

Spontaneous rupture of membranes
• "Waters break."
• Regular observations of mother and foetus.
• If >24 hours to deliver - paediatric care for infant.
• If >72 hours to delivery - induce.

Cervical changes
• Hormonal effects thin cervix (effacing).
• The show.
• Mechanical effects cause cervix to dilate.
• Dilates up to 4cm in early (latent) phase of labour).
• Dilation of >2cm considered "in labour."

Changes in contractions
• Natural rhythmic smooth muscle contractions through late pregnancy.
• Hormonal and mechanical changes cause alteration to contractions.

Remember!
• Pregnancy, labour and birth are normal.
• Physiology, not pathology.

Where to now?
• Home versus hospital.
• Individual decision.
• Majority of babies delivered in hospital.
• ≈30 home births per year in Liverpool region.
• Philosophical, resource, midwifery and legal issues.

Home births
• Ante-natal preparation and perinatal monitoring.
• Uncomplicated pregnancies with expected normal labour and delivery.
• Primiparous women accepted.
• Patients given information on safety of home births.
• Initial home visit in second trimester to check environment.
• Second visit at 35+ weeks to ensure equipment delivered and confirm birth plane.
• Patient contacts delivery suite as normal at onset of labour.
• Two midwives at birth.
• Problems lead to 999 transfer to hospital.

Pain relief in labour - non-pharmacological methods
• Support.
• Position.
• Mobilisation.
• Complementary therapies - massage, acupressure, aromatherapy, music etc.
• Water.
• TENS.

Pharmacological methods
• Paracetemol.
• "Gas and air" (nitrous oxide and oxygen in 1:1 ratio).
• Opiates - pethidine (less crosses into foetal circulation).
• Epidural (not home births).

Progression of labour
Stage 1
• Latent phase - up to 8 hours, gradual increase in strength of contraction.
• Active phase - up to 6 hours, contractions become more painful.
• Transitional phase - ≈1 hour, painful contractions.
• Progression from latent to active phase heralds time to call delivery suite.
• Progression variable, but overall labour 12-14 hours for primiparous women (6-7 hours for multiparous women).

Stage 2 - delivery
• Vaginal canal fully relaxed, cervix fully dilated.
• Frequent and strong prolonged contractions.
• Irresistible urge to push.

Stage 2 - birth
• Perineal bulging - emptying of residual bowel/bladder contents.
• Crowning of baby's head.
• Check cord position.
• Two midwives attend birth.
• Head delivered, followed by shoulders.
• Baby delivered in ≈1 hour from start of second stage.

In-patient care and support - paediatricians
• APGAR scores at 1 and 5 minutes (and 10 minutes if problems).
-Pulse.
-Breathing.
-Movements.
-etc.
-7-10 normal, 4-7 resuscitative support, 0-3 emergency resuscitation.

Episiotomy
• Some controversy, less common now.
• Performed to prevent uncontrolled tearing/need for caesarean section.
• Indication - large head, need for forceps.

Stage 3 - placenta
• 20-25cm, 500g.
• Smooth with central cord on uterine cavity (baby) side.
• Uterus relaxes after stage 2 for 10-15 minutes.
• As contraction restart, placenta shears away from uterine wall.
• Delivered via gentle consistent pressure on cord with above pressure to control descent.
• Must examine placenta to ensure intact.
• Post-partum haemorrhage - >500ml blood loss.
• Medical emergency usually due to failure of uterus to contract or placenta remnants.
• Risks reduced by routine syntocinon.
• Vaginal tears/episiotomy should be repaired immediately after delivery.

Caesarean section
• Non-cephalic presentations.
• Multiple pregnancies.
• >1 previous caesarean section.
• Suspected/previous problems in delivery.
• Foetal distress.
• Failure to progress.

Midwives
• Baby care information.
• Feeding support - breast versus bottle.
• Maternal rest and support.
• Advice wrt wound care, cord care, lochia etc.
• Early signs of problems.
• Labour "debriefing."
• Administration advice.

Paediatrics
• Second check within 24 hours,
• Weight, height, head circumference.
• Face.
• Back.
• Digits.
• Genitals.
• General appearance and behaviour.

Going home
• Discharge.
• Midwife visits on first day at home.
• Further visits as needed, up to 28 days post-delivery.
• Eighth day visit for heel prick test.

Health visitor
• Statutory visit 10-14 days post-delivery.
• Establish relationship.
• Support feeding.
• Baby routine and ailments.
• Weight/growth monitoring.
• Depression monitoring - Edinburgh Post-Natal Depression Score (EPNDS).
• Subsequent visits as indicated.
• Open access clinics every 2 weeks.
• Post-natal groups.
• Positive parenting groups.
• Ongoing growth/development monitoring.
• Ongoing maternal support and monitoring.
• Open dialogue.

Post-natal depression
• 10% of women.
• Weeks or months post-delivery.
• Symptoms of depression.
• Poor bonding with baby.
• Feelings of failure and guilt.
• Lasts for months.

"Baby blues"
• 50% of women, 4-10 days post delivery.
• Tearful and irritable.
• Rapidly resolves.

Puerperal psychosis
• 1 in 500 women within 2 months of delivery.
• Personality change, agitation, depression.
• Threaten suicide or harm to baby.
• Requires prolonged in-patient treatment.

GP's role
• Massively reduced - post-natal role only.
• Contact parents after delivery.
• Support/advice as needed.
• Part of health care team.
• 6 week check.

6 week check
• Parental concerns and questions.
• Weight and head circumference.
• General behaviour and appearance.
• Palate and fontanelles.
• Motor tone, reflexes.
• Eyes, hearing and vocalisation.
• Cardiovascular system.
• Spine, hips, feet.
• Hernias, testes, genitalia.
• Health education and advice.
• Contraception.
• Parental/family support.

What Has Blood Got To Do With Babies?

2006-04-03T09:42:00.001Z

21.3.06

Normal haemostasis
• 3 players:
1. Blood vessel.
2. Platelets - form initial plug.
3. Coagulation factors - form fibrin clot.

Bleeding from injured vessel will cease if
1. Internal pressure = external pressure
eg. increased blood surrounding tissue → increased vasoconstriction → increased hypotension (blood pressure decreased).
2. Hole blocked by solid material
ie. platelet plug → fibrin clot.

Coagulation of blood
Essential reaction: Soluble fibringogen I ==> [Prothrombin IIa] ==> Fibrin clot Ia

Physiological changes in coagulation in pregnant women
Increased clotting factors
• Including Factor VIII.

Reduced coagulation inhibitors
• Protein S.
• Activated protein C resistance.

Factors unchanged
• Antithrombin.
• Protein C levels (functional impairment).

Blood transfusion - haemolytic disease of the newborn.

Blood group systems
• ABO antigens.
-Glycoproteins.
-Same protein backbone (15 amino acids).
-Variable terminal sugars:
§L-fucose "H."
§L-fucose + N'acetyl galactosamine "A."
§L-focose + D galactose "B."
• A and B genes code transferases for sugar addition.
• ABH antigens increase in strength from 0-3 years.
• Isoagglutinins (anti A, anti B) present from 6 months.

Mortality and morbidity of ABO incompatibility - intravascular haemolysis
• Death ~ 10%.
• Irreversible renal failure ~ 30%.
• Renal failure ~ 30%.
• Asymptomatic ~ 30%.

Rhesus system
• Rh antigens are proteins in red cell membranes. ? Function.
• 3 closely-linked genes.
-D (d).
-C (c).
-E (e).
• Most immunogenic and clinically significant = D.
• Haemolytic disease of newborn (HDN) - delayed transfusion reaction.
• Rh (D) group (anti-D and red cells) SPIN.
Positive }
} control
Negative }

Antenatal screening
• Booking clinic (12 weeks).
-ABO.
-Rh (D).
-Antibody screen (indirect).
• Third trimester (28 weeks).
-Repeat for all.
• More frequently for some.

Anti-D prophylaxis
• Offered to all Rh (D) negative women.
• 500 IU anti-D immunoglobulin at 28 weeks.
• 500 IU anti-D immunoglobulin at 34 weeks.
• 500IU anti-D immunoglobulin after delivery.

Red cell transfusion indications - avoid wherever possible
• Peri-operative loss >1,000ml.
• Depends on haemoglobin (Hb) pre-op.
• Depeneds on cardiovascular status.
• Tx Hb at 10G/dl - WRONG!

Pre-compatibility testing - electronic crossmatch
• ABO/Rh (D) group patient (recipient) red cells.
• Antibody screen patient plasma (IAT + enzyme).
• ABO/Rh (D) group red cells.
• Major crossmatch (IAT).

Module 1.09

2006-04-03T09:42:00.000Z

A New Arrival.
20.3.06 - 31.3.06.

Genetic Variation Of Immune Disorders

2006-04-03T09:41:00.000Z

17.3.06

Disregulated, excessive or absent immune responses → pathology.

Excessive: allergies eg. asthma, hay fever.

Autoimmune diseases eg. diabetes, rheumatoid arthritis.

Immunodeficiencies.

Immunoproliferative disorders.

CD4+ helper T lymphocytes provide cytokines and growth factors that serve as (usually) essential costimulants for B cell (antibody) and CD8+ cytotoxic T cell responses.

2 types of antigen receptor
1. Surface immunoglobulin on B cells.
-Recognise intact antigens outside cell, where most bacteria found.
2. Antigen receptor on T cells: T cell antigen receptor (TCR).
-Detect peptide antigens generated inside cell eg. viral and bacterial peptides.

Function of HLA molecules
• Originally identified as histocompatibility antigens in context of transplantation and pregnancy.
• Now know: main function to sample antigenic peptides and present them for screening by T cells.

HLA molecules
• Encoded on short arm of chromosome 6.
• Human major histocompatibility complex (MHC) gene complex contains 264 genes/pseudogenes.

MHC
1. Class I HLA
• Expressed on virtually all nucleated cell types.
-Not trophoblast.
-Not sperm.
• 3 important genes - HLA - A, B, C; multiple "alleles."
• Binds small peptides (form cytosol) and "presents" them to CD8+ (cytotoxic) T cells.

2. Class II HLA
• Expressed on antigen - presenting cells (APC) - macrophages, dendritic cells and B cells.
• 3 gene products, HLA - DR, DP, DQ; multiple "alleles."
• Binds peptides (from intracellular vesicles) and presents them to CD4+ (helper) T cells.

CD4 activation necessary for virtually all immune responses, so APC play pivotal role.

Each HLA allele (tissue type) binds different repertoire of antigenic peptides fo presentation to T cells.

Frequency of immunogenic peptides
• Average-sized protein of 60,000 molecular weight contains ≈ 500 amino acids.
• From defined anchor residues for each class I/II HLA molecule in any individual, would be (at best) only a few peptides that could be bound.
• Hence, low frequency of immunogenic peptides in any typical protein - immunogenic peptides will vary between individuals.

How is HLA polymorphism maintained?
1. Non-pathogen-driven mechanisms
• Spontaneous mutation and gene conversion rates?
• Maternal-foetal incompatibilities??
• Mating preferences?

2. Pathogen-driven mechanisms
• Heterozygote advantage.
• Rare allele advantage.

HLA and HIV
• Frequently-exposed HIV-negative individuals:
-HLA-A2, -A28; -DR13.
-Higher occurrence of cervical IgA anti-HIV.
• Fast progressors:
-HLA-A1, -A9, -A11, -A23, -A24; -B8, -B-35.

HLA-B53 and malaria
• Frequency of allele is ≈ 1% in Caucasian populations, but >50% in Gambians.
• HLA-B53 can bind peptide from malaria parasite that is a target for cytotoxic T cells.
• Selective advantage of allele in malaria-endemic regions.

HLA-A11 and EBV
• European EBV strains recognised by HLA-A11 restricted CD8+ cytotoxic T cells.
• In New Guinea (where HLA-A11 more frequent), EBV has mutated - no longer recognised by HLA-A11-restricted CTL.
• Here, parasite one step ahead of host.

EBV, HSV and certain adenoviruses can persist harmlessly after primary infection (illness), because they interfere with the cellular mechanisms of production, processing or presentation of antigenic peptide fragments of viral proteins.

HLA polymorphism important in humans.

Pregnancy: The Obstetrician's View

2006-04-03T09:40:00.001Z

16.3.06

Causes of improved mortality
• Improved medical care
-Infection control.
-Medical knowledge.
-Anaethetics.
-Drugs (antibiotics, oxtocins, antihypertensives, MgSO¬4).
-Diagnostic ability.
• Availability of care (NHS/transport).
• Improved maternal health.
• Education.
• Audit.
• Changes in parity.

International situation
• Huge disparity in health outcomes.
• Worst in sub-Saharan Africa.

Causes of maternal mortality (global)
• Haemorrhage ~ 25%.
• Sepsis ~ 15%.
• Unsafe abortions ~ 15%.
• Hypertension/eclampsia ~ 12%.
• Prolonged labour ~ 8%.
• Pre-existing disorders ~ 20%.

Africa's problems
• Delays in treatment.
-Women do not seek care.
§Traditional treatments used.
-Transport.
§Inadequate.
§Huge distances.
-Delays at institution.
• Organisation.
-Work overload.
-Low morale.
• Lack of facilities and supplies.
-Finance.

Goal: access to quality care when needed.

Worst case - Sierra Leone
• Worst health indicators - UN WDI.
• Life expectancy = 37 years.

Work experience - South Africa
• 1998-1999.
• Obstetrics and gynaecology.
• Eastern Cape.
-Old "white" and township facilities.
• High-risk obstetrics.
-Eclampsia/antipartum haemorrhage/postpartum haemorrhage.
-High maternal mortality.

Philosophy of care
• "Pregnancy is a physiological process."
• WHO objectives for maternity care:
1. Healthy mother.
2. Healthy baby.
3. Good experience.
• Reality: "Pregnancy is only normal in retrospect."
• Risk assessment unhelpful.

Midwives see normal, obstetricians see abnormal
• Midwives better at screening.
• Gives obstetricians biased view.
• Labour becoming medicalised.

Medicalisation of birth
• Global rise in C-section rates.
• 90% in Brazil.
• At some time in some places, normal to have general anaesthetic to give birth.
• Upper class 30s women more at risk.
• Intervention leads of intervention.
• Academics tend to be medics not midwives.
• Power held with medical profession.
• Medics only see abnormal/complicated.
• Drives medicalisation and patient preference.

Reasons for caesarean section increase
• Society trends - convenience, control.
• Low threshold if foetal concerns.
• Safety of procedure.
• Patient preference.
• Medical ease.
• Litigation.
• Declining skills - complex vaginal deliveries.

Alternatives
• Hospital midwifery-led units.
• Community birth centres.
• Home birth.
• Birth Choice UK.
-Information on birth statistics.
-Different units.
Intervention rate.
• National Childbirth Trust.
-Established 1957.
-Independent.

Obstetrician's role in pregnancy
1. Pre-conceptual
• Counselling.
• Optimise medical conditions.
• Advise against pregnancy.
-Severe renal disease.
-Pulmonary hypertension.

2. Pre-natal
• Screening issues.
• Down's/spina bifida.
• Invasive testing.

3. Antenatal
• General obstetrics.
• Medical disorders.
• Foetal medicine.

4. Delivery
• IOL decisions.
• Manage abnormal labour.
• Operative delivery.
• HDU care.

5. Post-natal
• Counselling.
-Problems.
-IUFD.
-Referral.
• ?? Ongoing care eg. hypertension.

Liverpool Women's Hospital labour ward - tertiary care
• 24-hour cover.
• Multidisciplinary team.
-3 obstetricians.
-2 anaesthetists.
-12 midwives.

The future?
• Pre-natal implantation diagnosis.
• Non-invasive diagnosis.
-Genetic conditions.
-Free foetal DNA in maternal blood.
§Molecular genetics.
§Endless possibilities.
• Earlier identification of problems - USS 11-14 weeks.
• Effective interventions for:
-PET, preterm labour.
• Foetal surgery - spina bifida, diaphragmatic hernia, twin laser.
• Delivery by caesarean section??

Job in obstetrics?
• Recruitment crisis.
• Poor work-social balance.
• Consultant resident on-call.
• Fear of litigation.

Genetic Screening... But Why?

2006-04-03T09:40:00.000Z

15.3.06

Many questions, information needed
• What happened, why, what caused it?
• Whose fault was it? What can I/we do?
• Will it get better, is there a treatment?
• Will it happen again? Worse next time?
• What are our options? Are there any tests?
• Who else it at risk? Can they be tested?
• What can I do? Who can help us?

Clinical genetics package
• Genetic nurses/counsellors, MDT, medics.
• Home visits, pre-clinic contact, family history.
• Information gathering and consent; set them at ease.
• Genetics clinic - investigation, assessment.

Autosomal recessive
• Affected siblings [males] = [females].
• Parents usually unaffected carriers.
• 25% recurrence risk.
• Syndromes tend to breed true.
• Consanguinity, isolated populations.
• Founder effect versus selective advantage.
• Very, very low mutation rate.
• Non-paternity more likely.

Autosomal recessive conditions
• Cystic fibrosis.
• Sickle cell, thalassaemia - contiguous.
• Albinism.
• Hunter syndrome.

CF and carriers
• Everyone carries ≈5 recessive genes.
• Eg. sickle cell, thalassaemia, CF, Tay-Sachs.
• Consanguinity, making people aware.
• Population screening? When? How?

Genetic screening programmes
• During antenatal care, Down's screening.
• Haemoglobinpathies.

What are we going to do?
• Do nothing.
• Denial, hope for best.
• Public Health agenda, ££ costs.
• Eugenics.
• Give people choices and chances.

Population screening programmes
• Guidelines for new programmes. Who decides?
• Impact of genetic screening on extending family.
• Public Health agenda? Eugenics, ethical issues.

Types of genetic disease
• Chromosome disorders.
• Structural re-arrangements, translocations.

How important are genetic diseases?
• Individually rare, collectively common.

Influence of nature and nuture
• Multi-factorial.

Objectives of medical genetics
• 1X, specialist opinion, syndrome diagnosis.

Variation in human genome
• Single nucleotide polymorphism (SNP).
• Highly polymorphic markers.
• Anonymous sequences.
• Not causing disease, simply genetic flags.
• Frequent SNPs every 500-1,000 base pairs.
• Makes us varied and interesting.

Human Genome Project - deliverables
• Pharmacogenetics.
• Decreased toxicity/tailor therapy.

Applying new technologies
• Diagnostic testing.

Perinatal Epidemiology

2006-04-03T09:39:00.000Z

14.3.06

Definitions
Perinatal period
• From 24th completed weeks' pregnancy until end of 6th day of life.
• Includes stillbirths.
-Child which has issued forth from mother after 24th weeks of pregnancy.
-Did not at any time after being completely expelled from mother breathe or show other signs of life.

Epidemiology
• Study of distribution and determinants of health-related states/events in specific population.
• Application of study to promote, protect and restore health.
• Person, place, time.

Birth, fertility, mortality
• Crude birth rate.
-Total population.
• Fertility rates.
-Women 15-44 years.
§General.
§Age-specific.
§Total (period).
• Mortality rates.
-Live and stillbirths.
§Still birth.
§Perinatal.
-Live births.
§Neonatal (28 days).
•Early/late.
§Post-neonatal.
§Infant.

Sources of data
• Routine data collection (descriptive epidemiology study).
-Birth registration.
-Death/stillbirth registration.
-Birth notification.
• "Special" data collecting.
-Hospital audit.
-Special studies.
§Cross-sectional.
§Cohort.
§Case control.
§RCTs.

Registration and notification processes
Birth registration
• LEGAL DUTY to register birth within 42 days.
• Usually by parent.
-Infant: name, sex, weight of infant (from notification [record linkage]), plurality.
-Mother: name, address, date and place of birth, occupation.
-Father (if joint-registered or married): as with mother.
-If married: date of marriage, number of previous children (live and stillborn).
• International variations.

Birth notifications
• Responsibility of persons delivering infant.
-Within 36 hours of birth.
• Alerts NHS to birth and hence need for services, triggers NHS number.
-Linked to immunisation and screening in childhood.
• Includes birth weight, gestation and foetal anomalies.
-Record linkage with registration (birth weight).

Birth and infant mortality rates
Headline figures (England and Wales, 2001)
• How many births annually?
594, 634 live births.
-304,635 male (51.2%. F:M ratio = 1:1.050)
-356,548 "within marriage" (60%).
• How many stillbirths?
3,159 stillbirths.
-5.3 per 1,000 live and still births.
-1,725 male (F:M ratio = 1:1.203).
-1, 771 "within marriage" (56%).
• How many deaths?
3,240 deaths under 1 year.
-5.4 per 1,000 live births.
1,420 deaths aged 1-14 years.
-15 per 100,000 population of same age.

So what?
• Time, person, place.
• Descriptive epidemiology study.

Implications and consequences
• Declining birth rate.
-17% fall in crude birth rate in 11 years, compared with 13% fall in general fertility rate.
• Increasing maternal rate.
-18 months in 10 years.
• 7% fall in stillbirths.

Teenage pregnancies
• Peak of 9.5 (1996), trough 8.1.

Drug Safety In Pregnancy

2006-04-03T09:38:00.000Z

13.3.06

Primum non nocere ("First, do no harm").
• Mother.
• Child.

Adverse drug reactions
• Appreciably HARMFUL of UNPLEASANT reaction, resulting from intervention related to USE of medicinal product, which predicts hazard from future administration and warrants prevention or specific TREATMENT, or ALTERATION of dosage regimen, or WITHDRAWAL of product.
• Common.
• 6.2% of all hospital admissions.
• Occupy seven 800-bed hospitals in UK.

Drug safety in pregnancy
• Pre-existing disorders eg. epilepsy.
• Infections eg. urinary tract infections.
• Disorders of pregnancy.
• Treatment of foetus.

Physiological changes in pregnancy
Absorption…
• Decrease in intestinal motility.
• Decreased gastric emptying.
• Emesis/reflux - decreased absorption.

Distribution…
• Increased plasma volume by 45% (32 weeks).
• Total body fat increased.
• Protein concentration decreased.
• Uterine blood flow increased (<1% to 16-25%).

Excretion…
• 50% increase in glomerular filtration rate by mid-pregnancy.
• Increased excretion of drugs, increased dose requirements.

Bacteriuria in pregnancy…
• 6% of normal pregnant women have asymptomatic bacteriuria.
• 23-40% of these will develop acute pyelonephritis.
• Screening at initial test.
• For E. coli, commonly.

Treatment…
• Asymptomatic.
-Trial of single-dose therapy.
-If fails, 7-day course.
• Safe: penicillins and nitrofurantoin.
• Contraindicated: quinolones, tetracycline and trimethoprim.
• Symptomatic UTI: 1-2% pregnant women.
• Prevent complication to mother and foetus.
• Prevent recurrence.
• Ampicillin 10-14 day course.

Adverse effects of penicillins
• Nausea.
-Pregnancy can cause nausea.
-UTI may cause nausea.
-Drug can cause nausea.
• Diarrhoea.
-Vary in severity.
-Mild to fulminant colitis.
• Rash.

Causality
• Pregnancy-related?
• Disease-related?
• Drug-related?
• Temporal relationship.
• Rechallenge.
• Exclusion of other causes.
• Previous reports.
• ALWAYS CONSIDER DRUGS IN DIFFERENTIAL DIAGNOSIS OF NEW SYMPTOMS.

Placental circulation

Placental transfer
• Molecular weight of drug <500 daltons.
• Lipid solubility.
• Degree of ionisation of drug.
• Extent of plasma protein binding.
• Type I (intermediate).
-Equal concentrations.
-Complete transfer profile.
• Type II (most unsafe for foetus).
-Higher foetal than maternal plasma concentrations.
• Type III (safest for foetus).
-Higher maternal concentrations.
-Incomplete transfer profile.

Teratogenicity
• Regard every drug as being potentially teratogenic.
• 1-5% all congenital anomalies caused by drugs.
• Thalidomide disaster.
• Yellow card adverse drug reaction reporting scheme.

Yellow cards
• Introduced in 1964.
• 500,000 reports.
• ≈20,000 reports per year.

Screening for teratogenicity…
• Animals used as models for man.
• 2 species (rat/mouse + rabbit).
• 3 dose levels.
• Period of organogenesis.
• Males tested for effect on fertility.
• Females administered drug in third trimester to assess effects on foetal growth.

Stage of pregnancy…
• Period of organogenesis.
• Late stages may lead to foetal growth retardation and/or mental retardation.

Most teratogenic drugs during pregnancy:
• Alcohol.
• Anticonvulsants.
• Thalidomide.
• Corticosteroids.
• Vitamin A and derivatives.

Sources of information
• BNF.
• Drug information centres.
• National Teratology Information Centre, Newcastle.

Prescribing in pregnancy
• Disease pre-pregnancy.
-Does drug therapy need to be continued?
-Does it need to be altered?
• Try non-drug treatment first.
• Avoid multiple drugs.
• Select safest and most efficacious drug.
• Dose changes may be necessary.

Adverse drug reactions in pregnancy
• Consider stopping drug.
• Treat mother.
• If harm to foetus suspected, get specialist advice.
• Communication with mother.
• Report adverse reaction.

Complementary Medicine In The Community

2006-04-03T09:36:00.000Z

Okay, now Flintoff's holed out to deep mid-wicket. It just gets worse and worse. I think I'm going to cry. This is all too much, coupled with yesterday's "history-making" first UK number 1 on downloads only. So says the England cricket-supporting, vinyl-loving plenary-goer.

8.3.06

Why complementary medicine?
• Patients ask for information and referral.
• Should understand patients' choices.
• To broaden scientific horizon.
• Part of medical curriculum, so subject is assessed.

Conventional medicine
• Disease focus: organ.
• One local cause → specific symptoms.
• Mind and body = separate entities.
• Treatment = eliminating symptoms.

Complementary medicine
• Complex system.
• Multiple factors → systemic symptoms.
• Mind and body = two sides of one coin.
• Treatment = reinforcing the system.

Conceptual link: complexity
A complex system
• Contains many elements: multifactorial.
• Non-linear dose-response effects.
• Emerging properties unexplainable from properties of each element.
• Adaptative, self-organising.
• Memory established [Plesk and Greenhalgh, 2001].

Why do people use complementary medicine? They have:
• Poorer health.
• Higher education → autonomy for treatment choice.
• Profound life experiences transformed their world view: "Illness is part of my existence, rather than a disturbing factor" [Astin, 1998].

Main complementary therapies
• Acupuncture - traditional Chinese medicine.
• Homeopathy - within NHS (since 1948).
• Herbal medicine.
• Manipulative therapies: chiropraxy, osteopathy.
• Smallwood report (2005):
Complementary therapies → £480million possible savings on drugs prescriptions.

Referral pattern
Referral initiated by
1. GPs.
2. Patients.
3. Hospital doctors.
4. Others.

Reasons for choice of complementary medicine
• Conventional treatment not effective.
• Worries about side effects.
• Personal preference.
• Problems with side effects.

Changes other aspects
• Satisfaction ~90%.
• Secondary problems better ~ 33%.
-Mental: anxiety, depression.
-Pain, arthritis.
-Skin.
-Digestive.

Effect of RCT in homeopathy
• Otitis media.
• Osteoartritis.
• Childhood diarrhoea.
• Fibrositis.
• Hayfever, flu.
• Pain.

Evidence for acupuncture
• Conclusive.
-Dental pain.
-Nausea, especially postoperative.
-Migraine.
• Nonconclusive.
-Asthma.
-Back pain.
-Drug dependency.
-Tension headache, neck pain.
-Osteoarthritis.
-Stroke.

Integrative medicine
Organ and system approach combined
Type I → Type II ← Type III
Illness Reaction Person

Antenatal Care In The Community

2006-04-03T09:27:00.000Z

I'm currently feeling very depressed about the cricket. Matt Prior has just run himself out and I'm really regretting getting up at 4.30am (again!) to listen to a losing cause.

"I'm so glad to have you and it's getting worse/I'm so mad to love you and your evil curse..."

7.3.06

Community?
• "Shared care" - package of care carried out in community and secondary care - determined by clinical need.
• "Shared" notes - kept by patient.

Low-risk pregnancy: mainly midwife-/GP-led in the community.
High-risk pregnancy: mainly specialist-led in secondary care.

Why?
• Reduce maternal mortality and morbidity.
• Reduce neonatal mortality and morbidity.

What is it?
• Means of trying to ensure physical and emotional well-being of the pregnant woman.
• Ensure baby is in best physical health following delivery.
• Combination of screening and surveillance - designed to detect problems/abnormalities which might increase maternal and/or neonatal mortality and morbidity.
• Also seeks to address need to health promotion, information and choice for pregnant women.

Low-risk pregnancy
• Use specific criteria (16• Can move from low-risk to high-risk at any time in pregnancy.

History
• Confirm pregnancy - β hCG - early-morning urine sample.
• Age.
• Past menstrual history.
• Past gynaecological history.
• Past obstetric history.
• Medication.
• Social history.
• Family history.

Nice guidelines: www.nice.org.uk ~ 2003

Lifestyle advice
• Smoking - cigarettes/cannabis.
• Alcohol.
• Exercise.
• Travel - seatbelts/deep vein thromboses.
• Prescriptions.
• Complimentary therapies.
• Sexual activity.

Diet and food
• High fibre, low fat.
• Supplements: folic acid 400 mcg per day until 12 weeks.
• Avoid vitamin A supplements and liver.
• Avoid:
-Mould-ripened cheese eg. brie.
-Pate.
-Uncooked/undercooked ready-made meals.
-Raw/partially-cooked eggs and mayonnaise.

Toxoplasmosis
• Avoid contact with cat faeces and soil that may have traces of cat faeces in it.

Advice
• Screening and surveillance (main condition = Down's syndrome).
• Antenatal and parentcraft classes.
• Options wrt place of delivery, pain relief.
• National Childbirth Trust (NCT).

Overview Of Embryology

2006-04-03T09:25:00.000Z

Another of Dangerfield's, I'm afraid.

6.3.06

• Ovarian cycle and ovulation.
• Post-fertilisation to implantation.
• Blastocyst.
• Implantation.
-Epiblast (ectoderm) and hypoblast (endoderm).
• Bilaminar disc.
• Implantation and placenta.
• Primary villus formation.
• Secondary villus formation.
• Tertiary villus formation.
• Intervillus space.
• Placental structure.
• Cotyledons.
• Early foetal circulation.
• Late foetal circulation.
• Placental growth.
• Umbilical cord.
• Twins.

Gastrulation
Third week of gestation
• Establishes three germ layers:
1. Ectoderm.
2. Mesoderm.
3. Endoderm.
• Involves formation of primitive streak.

• Trilaminar disc formation.
• Primitive streak.
• Notochord and neuroenteric canal.
• Neural tube and mesoderm.
• Somite and mesoderm.
• Migration of sclerotome.